The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(−)-PPO464

Name: Work Video:
Duration: 3 min 30 s
Giovanni Maga; Anna Ramunno; Vito Nacci; Giada A. Locatelli; Silvio Spadari; Isabella Fiorini; Fausto Baldanti; Stefania Paolucci; Maurizio Zavattoni; Alberto Bergamini; Bruno Galletti; Sandra Muck; Ulrich Hübscher; Gianluca Giorgi; Giovanna Guiso; Silvio Caccia; Giuseppe Campiani
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'https://www.wikidata.org/wiki/Q2528140', 'display_name': 'Viral load', 'level': 3, 'score': 0.11818275}, {'id': 'https://openalex.org/C104317684', 'wikidata': 'https://www.wikidata.org/wiki/Q7187', 'display_name': 'Gene', 'level': 2, 'score': 0.07607818}, {'id': 'https://openalex.org/C2993143319', 'wikidata': 'https://www.wikidata.org/wiki/Q583050', 'display_name': 'Antiretroviral therapy', 'level': 4, 'score': 0.0}], 'mesh': [{'descriptor_ui': 'D001381', 'descriptor_name': 'Azepines', 'qualifier_ui': 'Q000493', 'qualifier_name': 'pharmacokinetics', 'is_major_topic': True}, {'descriptor_ui': 'D001381', 'descriptor_name': 'Azepines', 'qualifier_ui': 'Q000494', 'qualifier_name': 'pharmacology', 'is_major_topic': True}, {'descriptor_ui': 'D054303', 'descriptor_name': 'HIV Reverse Transcriptase', 'qualifier_ui': 'Q000378', 'qualifier_name': 'metabolism', 'is_major_topic': True}, {'descriptor_ui': 'D011725', 'descriptor_name': 'Pyridines', 'qualifier_ui': 'Q000493', 'qualifier_name': 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'Q000187', 'qualifier_name': 'drug effects', 'is_major_topic': False}, {'descriptor_ui': 'D001812', 'descriptor_name': 'Blood-Brain Barrier', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D018360', 'descriptor_name': 'Crystallography, X-Ray', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D004305', 'descriptor_name': 'Dose-Response Relationship, Drug', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D054303', 'descriptor_name': 'HIV Reverse Transcriptase', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D007700', 'descriptor_name': 'Kinetics', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D008297', 'descriptor_name': 'Male', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D051379', 'descriptor_name': 'Mice', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D008956', 'descriptor_name': 'Models, Chemical', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D009154', 'descriptor_name': 'Mutation', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D011485', 'descriptor_name': 'Protein Binding', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D011725', 'descriptor_name': 'Pyridines', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D051381', 'descriptor_name': 'Rats', 'qualifier_ui': '', 'qualifier_name': None, 'is_major_topic': False}, {'descriptor_ui': 'D011994', 'descriptor_name': 'Recombinant Proteins', 'qualifier_ui': 'Q000378', 'qualifier_name': 'metabolism', 'is_major_topic': False}, {'descriptor_ui': 'D011994', 'descriptor_name': 'Recombinant Proteins', 'qualifier_ui': '', 'qualifier_name': None, 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'https://openalex.org/W2003299861', 'https://openalex.org/W1985622714'], 'abstract_inverted_index': {'The': [0, 71, 213, 236, 307, 449, 508, 649, 1380, 1449, 1565, 1623, 1665, 1680, 1755, 1780, 1806, 1959, 2009, 2185, 2254, 2277, 2311, 2345, 2436, 2841, 3003, 3509, 3596, 3773, 3814, 3936, 4138, 4314], 'human': [1, 237, 472], 'immunodeficiency': [2, 238, 473], 'virus': [3, 239, 474, 4226, 4355], 'type': [4, 23, 100, 180, 240, 259, 336, 416, 475, 837, 916, 1176, 1263, 2725], '1': [5, 241, 476, 1720, 2469, 2536, 2547, 2582, 3320, 3651, 3656, 3662, 4006, 4085, 4121, 4127, 4134], '(HIV-1)': [6, 242], 'nonnucleoside': [7, 149, 243, 385, 479], 'reverse': [8, 244, 477, 480, 484], 'transcriptase': [9, 245, 478, 481, 485, 511], '(RT)': [10, 246, 512, 3132], 'inhibitor': [11, 219, 247, 455, 482, 486, 488, 2705, 3039, 3097, 3202, 3332, 3373, 3406, 3419, 3437], 'pyrrolopyridooxazepinone': [12, 248, 489], '(PPO)': [13, 249], 'derivative,': [14, 250], '(±)-PPO294,': [15, 251], 'was': [16, 74, 84, 108, 204, 252, 310, 320, 344, 440, 1403, 1452, 1567, 1607, 1627, 1662, 1667, 1684, 1733, 1757, 1811, 1845, 1953, 1962, 1973, 1987, 1994, 2002, 2012, 2149, 2189, 2252, 2256, 2279, 2322, 2385, 2402, 2416, 2442, 2488, 2564, 2662, 2696, 2728, 2760, 2828, 2867, 2921, 2982, 3356, 3388, 3498, 3512, 3600, 3791, 3817, 4144, 4257, 4290, 4308, 4319, 4451, 4494], 'shown': [17, 253, 943, 2928, 3338, 3425], 'to': [18, 29, 110, 136, 207, 254, 265, 346, 372, 443, 567, 618, 641, 716, 769, 865, 902, 913, 944, 1018, 1033, 1084, 1160, 1292, 1413, 1616, 1786, 1976, 2125, 2151, 2349, 2451, 2492, 2543, 2600, 2717, 2749, 2763, 2959, 2971, 2984, 2989, 3056, 3073, 3076, 3305, 3314, 3358, 3390, 3448, 3477, 3520, 3547, 3559, 3604, 3666, 3783, 4008, 4022, 4041, 4054, 4133, 4266], 'be': [19, 255, 1085, 2985, 3074, 3178, 3245, 3964, 4111], 'active': [20, 256, 999, 1308], 'toward': [21, 257], 'wild': [22, 99, 179, 258, 335, 415, 836, 915, 1175, 1262, 2724], 'and': [24, 28, 80, 101, 107, 125, 163, 189, 232, 260, 264, 316, 337, 343, 361, 399, 425, 468, 520, 588, 616, 653, 690, 839, 917, 969, 1098, 1139, 1177, 1249, 1258, 1282, 1323, 1335, 1372, 1416, 1426, 1518, 1551, 1557, 1586, 1598, 1764, 1768, 1776, 1784, 1795, 1971, 1991, 2007, 2121, 2181, 2365, 2374, 2391, 2396, 2407, 2430, 2468, 2479, 2490, 2524, 2609, 2650, 2657, 2659, 2755, 2796, 2825, 2861, 2999, 3012, 3041, 3053, 3059, 3070, 3080, 3103, 3133, 3221, 3232, 3253, 3259, 3408, 3459, 3470, 3489, 3543, 3551, 3590, 3612, 3630, 3632, 3659, 3702, 3730, 3804, 3827, 3868, 3924, 4013, 4048, 4130, 4157, 4259, 4338, 4353, 4367, 4373, 4382, 4415, 4418, 4434, 4479, 4491, 4517], 'mutated': [25, 261, 918, 1178], 'HIV-1': [26, 105, 174, 217, 262, 341, 410, 453, 583, 614, 766, 947, 1254, 2676, 2719, 2834], 'RT': [27, 106, 119, 161, 263, 342, 355, 397, 615, 697, 711, 767, 1256, 2487, 2677, 2720, 2835, 2932, 3213], 'act': [30, 266, 1012, 4101], 'synergistically': [31, 267, 1013], 'in': [32, 157, 187, 268, 393, 423, 579, 664, 695, 709, 1002, 1030, 1087, 1153, 1370, 1378, 1385, 1456, 1719, 1944, 1989, 1997, 2119, 2191, 2195, 2262, 2368, 2447, 2458, 2554, 2636, 2645, 2652, 2698, 2708, 2736, 2743, 2894, 2929, 2987, 3339, 3426, 3578, 3624, 3736, 3739, 4028, 4059, 4102, 4113, 4240, 4279, 4332, 4342, 4363, 4387, 4395, 4453, 4474], 'combination': [33, 158, 269, 394, 1003, 1089, 1154, 3626, 3672, 3712, 3738, 3876, 4029], 'with': [34, 113, 121, 159, 270, 349, 357, 395, 586, 639, 831, 907, 1004, 1014, 1026, 1135, 1170, 1290, 1330, 1356, 1579, 1641, 1697, 1771, 1837, 2004, 2140, 2161, 2942, 2953, 2968, 2975, 3160, 3214, 3218, 3697, 4030, 4261, 4292, 4389, 4397], '3′-azido-3′-deoxythymidine': [35, 271, 491, 492], '(Campiani,': [36, 272], 'G.,': [37, 45, 51, 55, 273, 281, 287, 291], 'Morelli,': [38, 274], 'E.,': [39, 47, 59, 275, 283, 295], 'Fabbrini,': [40, 276], 'M.,': [41, 277], 'Nacci,': [42, 278], 'V.,': [43, 279], 'Greco,': [44, 280], 'Novellino,': [46, 282], 'Ramunno,': [48, 284], 'A.,': [49, 57, 285, 293], 'Maga,': [50, 286], 'Spadari,': [52, 288], 'S.,': [53, 65, 289, 301], 'Caliendo,': [54, 290], 'Bergamini,': [56, 292], 'Faggioli,': [58, 294], 'Uccella,': [60, 296], 'I.,': [61, 297], 'Bolacchi,': [62, 298], 'F.,': [63, 299], 'Marini,': [64, 300], '(1999)J.': [66, 302], 'Med.': [67, 303, 550, 1119, 1225, 1489], 'Chem.': [68, 304, 1226, 1490], '42,': [69, 305], '4462–4470).': [70, 306], '(±)-PPO294': [72, 308, 1186, 1252, 1714, 4470], 'racemate': [73, 309, 1566], 'resolved': [75, 311, 1568, 1734], 'into': [76, 312, 2551, 2687], 'its': [77, 134, 230, 313, 370, 466, 3215], 'pure': [78, 314, 2030], 'enantiomers,': [79, 315], 'the': [81, 98, 102, 114, 123, 126, 130, 142, 171, 200, 210, 216, 222, 317, 334, 338, 350, 359, 362, 366, 378, 407, 436, 446, 452, 458, 500, 516, 568, 571, 580, 619, 622, 631, 642, 646, 654, 696, 699, 710, 719, 745, 757, 821, 835, 857, 871, 889, 894, 900, 914, 988, 1079, 1088, 1130, 1166, 1183, 1236, 1242, 1266, 1274, 1304, 1361, 1364, 1406, 1427, 1519, 1525, 1610, 1711, 1765, 1809, 1817, 1985, 1992, 1999, 2123, 2192, 2196, 2263, 2297, 2315, 2319, 2325, 2378, 2381, 2387, 2417, 2420, 2452, 2544, 2671, 2675, 2699, 2709, 2744, 2833, 2847, 2851, 2857, 2863, 2880, 2884, 2907, 2924, 2954, 2961, 2969, 3006, 3017, 3034, 3037, 3051, 3057, 3077, 3085, 3092, 3112, 3126, 3129, 3134, 3142, 3155, 3174, 3187, 3208, 3229, 3233, 3239, 3248, 3257, 3267, 3302, 3306, 3315, 3325, 3331, 3334, 3349, 3353, 3359, 3366, 3372, 3375, 3391, 3397, 3402, 3412, 3418, 3421, 3445, 3449, 3464, 3478, 3486, 3492, 3501, 3515, 3538, 3556, 3560, 3566, 3574, 3579, 3582, 3586, 3607, 3614, 3617, 3625, 3635, 3667, 3711, 3717, 3737, 3740, 3744, 3789, 3794, 3805, 3820, 3878, 3881, 3894, 3898, 3912, 3916, 3921, 3930, 3933, 3950, 3956, 3959, 3967, 3997, 4002, 4016, 4024, 4035, 4043, 4051, 4056, 4062, 4074, 4089, 4099, 4108, 4255, 4264, 4268, 4288, 4296, 4303, 4329, 4333, 4339, 4343, 4346, 4390, 4432, 4463, 4492, 4500, 4503], 'absolute': [82, 318, 2312, 3493], 'configuration': [83, 319, 2313], 'determined': [85, 321, 1315, 2173, 3205, 3442, 3475, 3995, 4145, 4320], 'by': [86, 118, 322, 354, 675, 749, 893, 1051, 1569, 1609, 1813, 2014, 2115, 2174, 2249, 2258, 2282, 2295, 2324, 2664, 2950, 3016, 3141, 3207, 3247, 3295, 3443, 3554, 3606, 3726, 3915, 4146, 4512], 'x-ray': [87, 323, 2152], 'analysis.': [88, 324], 'Only': [89, 325], 'one': [90, 326, 3870], 'enantiomer,': [91, 327], '(R)-(−)-PPO464,': [92, 225, 328, 461], 'displayed': [93, 329], 'antiviral': [94, 330, 527, 1082, 1283], 'activity': [95, 331, 1173, 2528, 2541, 2563, 2681, 2839], 'against': [96, 170, 177, 332, 406, 413, 834, 1174, 1253, 2870], 'both': [97, 122, 333, 358, 1247, 4114], 'K103N': [103, 339, 859, 1267], 'mutant': [104, 340], 'found': [109, 206, 345, 442], 'interact': [111, 347], 'exclusively': [112, 348, 3206], 'reaction': [115, 351, 1960, 2919, 2978, 2991], 'intermediate': [116, 352], 'formed': [117, 353], 'complexed': [120, 356], 'DNA': [124, 360, 2539, 2561, 2679, 2693, 2837], 'nucleotide': [127, 363], 'substrates.': [128, 364, 3216], 'Being': [129, 365], 'first': [131, 367, 720, 2941, 3510], 'compound': [132, 368, 1193, 1713, 4469], 'of': [133, 144, 148, 215, 224, 369, 380, 384, 451, 460, 504, 506, 564, 582, 645, 679, 688, 701, 718, 759, 762, 765, 824, 870, 873, 896, 951, 990, 997, 1081, 1132, 1151, 1168, 1244, 1246, 1251, 1306, 1363, 1524, 1554, 1605, 1659, 1677, 1710, 1722, 1774, 1808, 1938, 2029, 2111, 2134, 2238, 2272, 2306, 2314, 2360, 2372, 2380, 2383, 2389, 2392, 2419, 2427, 2449, 2533, 2538, 2546, 2549, 2571, 2597, 2684, 2692, 2701, 2704, 2740, 2746, 2767, 2788, 2813, 2853, 3005, 3050, 3114, 3118, 3210, 3212, 3301, 3330, 3348, 3371, 3417, 3436, 3570, 3581, 3616, 3637, 3673, 3713, 3721, 3743, 3777, 3788, 3796, 3825, 3877, 3907, 3932, 3945, 3958, 3977, 3987, 4004, 4018, 4037, 4076, 4091, 4117, 4141, 4150, 4213, 4225, 4243, 4254, 4287, 4305, 4328, 4345, 4436, 4502], 'class': [135, 371, 563], 'display': [137, 373], 'this': [138, 374, 874, 3891, 3946], 'behavior,': [139, 375], '(R)-(−)-PPO464': [140, 151, 197, 203, 376, 387, 433, 439, 1276, 1299, 3544], 'is': [141, 377, 513, 1144, 1376, 3014, 3031, 3139, 3157, 3167, 3190, 3198, 3204, 3324, 3365, 3396, 3401, 3411, 3456, 3485, 3491, 3565, 3573, 3585, 3592, 3753, 3897, 3911, 3920, 3926, 3939, 3993, 4015, 4034, 4050, 4069, 4073, 4084, 4088, 4096], 'representative': [143, 379], 'a': [145, 192, 381, 428, 523, 562, 576, 703, 1027, 1147, 1190, 1287, 1300, 1317, 1345, 1351, 1442, 1504, 1513, 1533, 1559, 1570, 1580, 1587, 1617, 1628, 1670, 1674, 1685, 1728, 1739, 1838, 1936, 2156, 2210, 2526, 2568, 2737, 2764, 2771, 2789, 2895, 3457, 3593, 3677, 3927, 3942, 3974, 4103, 4198, 4244, 4280], 'novel': [146, 382, 1133, 1296], 'generation': [147, 383, 668, 721, 826, 905, 1310], 'inhibitors.': [150, 386], 'showed': [152, 191, 388, 427, 1008], 'significant': [153, 389, 964], 'synergism': [154, 390], 'when': [155, 168, 391, 404, 3185, 3622, 3643], 'tested': [156, 169, 392, 405, 3623, 3644, 4324], 'other': [160, 396, 1293, 2424], 'inhibitors': [162, 398, 565, 638, 906], 'efficiently': [164, 400], 'inhibited': [165, 401, 3008], 'viral': [166, 402, 517, 569, 1259, 3908], 'replication': [167, 403, 518], 'laboratory': [172, 408], 'strain': [173, 409], 'IIIB': [175, 411], 'or': [176, 181, 412, 417, 957, 1058, 1264, 1349, 1511, 2434, 2694, 2726, 3871, 3979, 4105, 4472], 'either': [178, 414, 1261, 2723], 'multidrug-resistant': [182, 418], 'clinical': [183, 419, 665, 970, 991], 'isolates.': [184, 420], 'Pharmacokinetic': [185, 421], 'studies': [186, 422, 4360], 'mice': [188, 424, 4366], 'rats': [190, 426, 4369, 4509], 'more': [193, 429, 909, 1148, 1307, 3872], 'favorable': [194, 430, 910], 'profile': [195, 431], 'for': [196, 199, 432, 435, 515, 526, 613, 949, 1146, 1165, 1303, 1405, 1910, 1919, 1927, 1965, 2095, 2289, 2292, 2355, 2476, 2616, 2654, 2674, 2730, 2832, 2883, 2891, 2903, 2923, 3084, 3096, 3256, 3317, 3537, 3648, 3710, 3733, 3755, 3800, 3808, 3865, 3869, 3901, 4208, 4310, 4321, 4431], 'than': [198, 434, 955, 1056, 4120, 4126], 'corresponding': [201, 437, 2748, 2955, 3007, 3038, 3143, 4340], 'racemate.': [202, 438], 'also': [205, 441, 3186], 'easily': [208, 444], 'cross': [209, 445], 'blood-brain': [211, 447], 'barrier.': [212, 448], 'coadministration': [214, 450], 'protease': [218, 454, 487], 'ritonavir': [220, 456], 'increased': [221, 457], 'bioavailability': [223, 459], 'having': [226, 462], 'little': [227, 463], 'effect': [228, 464, 3568, 3576, 3823, 3903, 4011, 4027, 4046, 4058], 'on': [229, 465, 1344, 1350, 1392, 1441, 1503, 1512, 1532, 1558, 1646, 1702, 1727, 1738, 2155, 2177, 2287, 2529, 2627, 2822, 3352, 3514, 3793, 3819, 3955, 4220, 4231], 'plasma': [231, 467, 946, 4493], 'brain': [233, 469], 'elimination': [234, 470], 'rates.': [235, 471], 'nucleoside': [483], 'template-primer': [490], '5′-triphosphate': [493], 'high': [494, 1171], 'pressure': [495], 'liquid': [496], 'chromatography': [497, 1408, 2016], 'area': [498], 'under': [499, 1431, 1545, 2670, 2879, 3111, 3264, 3716, 4456, 4514], 'concentration-time': [501], 'curve': [502, 3938], 'sum(s)': [503], 'squares': [505, 3298], 'errors': [507], 'virus-encoded': [509], 'HIV-11reverse': [510], 'essential': [514], 'cycle': [519], 'therefore': [521], 'represents': [522, 3461, 3893], 'logical': [524], 'target': [525], 'chemotherapy': [528, 753], '(1Hübscher': [529], 'U.': [530], 'Spadari': [531, 1210, 1474], 'S.': [532, 846, 973, 1211, 1223, 1475, 1487], 'Physiol.': [533], 'Rev.': [534, 552, 809, 1118, 3529, 3766], '1994;': [535, 734], '74:': [536], '259-304Crossref': [537], 'PubMed': [538, 556, 598, 737, 799, 815, 851, 933, 981, 1042, 1070, 1108, 1124, 1230, 1494, 3839, 3854], 'Scopus': [539, 557, 599, 738, 800, 816, 852, 934, 982, 1043, 1071, 1109, 1125, 1231, 1495, 2338, 2520, 3840, 3855], '(49)': [540], 'Google': [541, 559, 601, 740, 802, 818, 854, 886, 936, 984, 1045, 1073, 1111, 1127, 1233, 1497, 2340, 2522, 3533, 3770, 3842, 3857, 4188], 'Scholar,': [542, 803, 1112, 3843], '2Jonckheere': [543], 'H.': [544], 'Anne': [545], 'J.': [546, 772, 784, 879, 1224, 1488, 2498, 2500, 3527, 3764, 3834], 'De': [547], 'Clercq': [548, 591, 727, 1036], 'E.': [549, 592, 728, 776, 1037, 1197, 1205, 1461, 1469, 4167], 'Res.': [551, 594, 977], '2000;': [553, 930, 978, 1067, 1105, 1121, 2512], '20:': [554], '129-154Crossref': [555], '(187)': [558], 'Scholar).': [560, 602, 741, 855, 887, 937, 985, 1046, 1074, 1128, 1234, 2276, 2310, 2341, 3858, 4189, 4218], 'Recently,': [561], 'targeted': [566], 'RT,': [570, 1179], 'so-called': [572], 'NNRTIs,': [573, 669], 'have': [574, 941, 1181, 1240, 3969], 'gained': [575], 'definitive': [577], 'place': [578], 'treatment': [581, 1034], 'infections': [584], 'along': [585], 'NRTIs': [587, 1005, 1015, 1057], 'PIs': [589, 1007, 1059], '(3De': [590], 'Antiviral': [593, 976], '1998;': [595, 848], '38:': [596], '153-179Crossref': [597], '(369)': [600], 'These': [603, 1295], 'compounds,': [604], 'despite': [605], 'their': [606, 684, 691, 4383], 'different': [607, 643, 680, 763, 2690, 2805, 2864, 2877, 2908, 3344, 3385, 3431, 3505], 'chemical': [608, 1365], 'structures,': [609], 'are': [610, 661, 1049, 1368, 1417, 1521, 2241, 3634, 3812, 4064, 4394], 'highly': [611, 998], 'specific': [612, 2527, 3741], 'bind': [617], 'enzyme': [620, 838, 2994, 3131], 'at': [621, 1438, 1673, 1735, 1759, 1950, 1968, 1982, 2127, 2235, 2318, 2444, 2473, 2483, 2557, 2619, 2689, 2733, 2770, 2773, 2804, 2815, 2856, 2862, 2876, 2906, 3125, 3169, 3182, 3238, 3343, 3378, 3384, 3404, 3430, 3676, 4250, 4276, 4485, 4496], 'same': [623, 1818, 4025, 4044, 4057], 'allosteric': [624], 'site': [625, 694], 'close': [626], 'to,': [627], 'but': [628], 'distinct': [629, 1288], 'from,': [630], 'catalytic': [632], 'site,': [633], 'behaving': [634], 'as': [635, 671, 724, 754, 756, 829, 995, 1092, 1189, 1358, 1454, 1751, 1803, 2020, 2032, 2495, 2566, 2706, 2830, 2913, 3033, 3045, 3064, 3337, 3424, 4159], 'typically': [636], 'noncompetitive': [637, 3275, 3282], 'respect': [640, 1291], 'substrates': [644, 3055], 'polymerization': [647], 'reaction.': [648, 2926], 'NNRTIs': [650, 722, 770, 994, 1010, 1048, 1134, 1152, 1169], 'nevirapine,': [651, 672, 3542], 'delavirdine,': [652], 'most': [655, 717], 'recently': [656], 'licensed,': [657], 'efavirenz': [658], '(Fig.': [659, 1187, 1277], '1),': [660], 'currently': [662], 'used': [663, 1086, 1404, 2190, 3094], 'practice.': [666], 'First': [667], 'such': [670, 723, 828, 1091, 3044], 'were': [673, 1314, 1324, 1328, 1342, 1382, 1390, 1422, 1429, 1436, 1501, 1530, 1782, 1835, 2113, 2172, 2233, 2410, 2426, 2614, 2624, 2633, 2642, 2668, 2713, 2802, 2820, 2873, 2889, 2910, 3062, 3071, 3293, 3311, 3441, 3474, 3507, 3545, 3552, 3688, 3724, 4195, 4229, 4273, 4357, 4361, 4385, 4467, 4483, 4489, 4510, 4519], 'identified': [674], 'extensive': [676], 'random': [677], 'screening': [678], 'molecules.': [681], 'However,': [682, 856], 'given': [683, 1369, 1377, 4468], 'very': [685], 'similar': [686, 3975, 4104], 'mode': [687, 3976, 3986], 'action': [689, 1245], 'unique': [692, 2242], 'binding': [693, 911, 2952, 2981, 3098, 3117, 3138, 3203, 3243, 3438], 'enzyme,': [698], 'occurrence': [700], 'just': [702], 'few': [704], 'single': [705, 858, 2132, 3450], 'amino': [706], 'acid': [707, 2649], 'substitutions': [708], 'gene': [712], 'can': [713, 861, 3177, 3244, 3963], 'confer': [714, 863], 'resistance': [715, 746, 1141], 'nevirapine': [725, 2904], '(4De': [726], 'Ann.': [729], 'N.': [730], 'Y.': [731, 788], 'Acad.': [732], 'Sci.': [733], '724:': [735], '438-456Crossref': [736], '(15)': [739], 'Accumulating': [742], 'knowledge': [743], 'about': [744, 4371], 'mutations': [747], 'selected': [748, 1182, 2180], 'these': [750, 3265], 'compounds': [751], 'during': [752], 'well': [755, 4242, 4307], 'resolution': [758], 'crystallographic': [760], 'structures': [761], 'complexes': [764, 3009, 3061, 3236], 'bound': [768], '(5Ren': [771], 'Esnouf': [773], 'R.': [774, 1063, 4179], 'Garman': [775], 'Somers': [777], 'D.': [778, 790, 792, 4175, 4177, 4181], 'Ross': [779], 'C.': [780, 921], 'Kirby': [781], 'I.': [782, 1219, 1483], 'Keeling': [783], 'Darby': [785], 'G.': [786, 1117, 1195, 1203, 1209, 1213, 1459, 1467, 1473, 1477, 3525, 3762, 4183], 'Jones': [787], 'Stuart': [789, 2505], 'Stammers': [791, 2507], 'Nat.': [793], 'Struct.': [794, 2509], 'Biol.': [795], '1995;': [796, 3530, 3767], '2:': [797], '293-302Crossref': [798], '(561)': [801], '6Erickson': [804], 'J.W.': [805], 'Burt': [806], 'S.K.': [807], 'Annu.': [808], 'Pharmacol.': [810, 929, 3528, 3765], 'Toxicol.': [811], '1996;': [812], '36:': [813], '545-571Crossref': [814], '(164)': [817], 'Scholar)': [819, 2523], 'allowed': [820], 'rational': [822], 'design': [823], 'second': [825, 3815], 'molecules,': [827], 'efavirenz,': [830], 'improved': [832, 1136], 'potency': [833], 'several': [840], 'resistant': [841], 'forms': [842, 3123], '(7Adkins': [843], 'J.C.': [844], 'Noble': [845], 'Drugs.': [847], '56:': [849], '1055-1066Crossref': [850], '(261)': [853], 'mutation': [860, 1142], 'still': [862], 'cross-resistance': [864, 1099], 'most,': [866], 'if': [867, 4079], 'not': [868, 1418], 'all,': [869], 'members': [872], 'subclass': [875], '(8Clotet': [876], 'B.': [877, 1061, 4204], 'Int.': [878], 'Clin.': [880, 1064, 1102], 'Pract.': [881], 'Suppl.': [882, 4403], '1999;': [883, 1039, 1227, 1491, 4185], '103:': [884], '21-25PubMed': [885], 'Thus,': [888], 'continuous': [890], 'challenge': [891], 'posed': [892], 'emergence': [895], 'HIV-1-resistant': [897], 'mutants': [898], 'highlights': [899], 'need': [901], 'develop': [903], 'third': [904, 1309], 'yet': [908], 'properties': [912, 1297], 'enzymes': [919, 1257], '(9Mao': [920], 'Sudbeck': [922], 'E.A.': [923], 'Venkatachalam': [924], 'T.K.': [925], 'Uckun': [926], 'F.M.': [927], 'Biochem.': [928, 3835], '60:': [931], '1251-1265Crossref': [932], '(78)': [935], 'Triple': [938], 'drug': [939, 1093, 1140, 3639, 3735, 3757, 3802, 3822, 4192, 4265, 4270, 4298, 4323, 4350], 'combinations': [940], 'been': [942], 'suppress': [945], 'load': [948], 'periods': [950], 'time': [952, 2806, 2859, 2865], 'significantly': [953], 'longer': [954], 'monotherapy': [956], 'dual': [958], 'therapy,': [959, 1090], 'allowing': [960, 2122], 'CD4T': [961], 'cell': [962, 4154], 'increase,': [963], 'immune': [965], 'system': [966], 'function': [967], 'restoration,': [968], 'improvement': [971, 1029], '(10Vella': [972], 'Palmisano': [974], 'L.': [975], '45:': [979], '1-7Crossref': [980], '(81)': [983], 'In': [986, 1156, 1235, 3890, 4190, 4348], 'particular,': [987], 'results': [989, 1270, 1520, 3795], 'trials': [992], 'employing': [993], 'components': [996], 'antiretroviral': [1000], 'therapy': [1001], 'and/or': [1006], 'that': [1009, 1272, 2966, 3750, 3948, 4019, 4393], 'often': [1011], 'and,': [1016], 'due': [1017], 'positive': [1019], 'pharmacokinetic': [1020], 'properties,': [1021], 'allow': [1022], 'simplified': [1023, 2918], 'administration': [1024], 'schedules': [1025], 'substantial': [1028], "patients'": [1031], 'adherence': [1032], '(11De': [1035], 'Farmaco.': [1038], '54:': [1040], '26-45Crossref': [1041], '(178)': [1044], 'Moreover,': [1047], 'characterized': [1050, 1241], 'less': [1052, 4119], 'severe': [1053], 'adverse': [1054, 1095], 'effects': [1055, 3972, 3982], '(12Max': [1060], 'Sherer': [1062], 'Infect.': [1065, 1103], 'Dis.': [1066, 1104], '30:': [1068, 1106], 'S96-S116Crossref': [1069], '(179)': [1072], 'Several': [1075], 'factors': [1076], 'may': [1077, 4110], 'restrict': [1078], 'selection': [1080], 'drugs': [1083, 3618, 3675, 3715], 'compatibilities,': [1094], 'side': [1096], 'effects,': [1097], "(13O'Brien": [1100], 'W.A.': [1101], 'S185-S192Crossref': [1107], '(42)': [1110], '14Telenti': [1113], 'A.': [1114, 1207, 1215, 1471, 1479, 2334, 4173], 'Paolo': [1115], 'Rizzardi': [1116], 'Virol.': [1120], '10:': [1122], '385-393Crossref': [1123], '(25)': [1126], 'Therefore,': [1129], 'development': [1131, 1167], 'pharmacological,': [1137], 'pharmacokinetic,': [1138], 'profiles,': [1143], 'critical': [1145], 'successful': [1149], 'application': [1150], 'therapy.': [1155], 'an': [1157, 1386, 1842, 2809, 2934, 2943, 2976, 3984], 'effort': [1158], 'aimed': [1159], 'identify': [1161], 'new': [1162], 'lead': [1163, 1192, 1302], 'molecules': [1164], 'inhibitory': [1172, 3588, 4316], 'we': [1180, 1239], 'PPO': [1184], 'derivative': [1185], '1)': [1188, 1278], 'promising': [1191, 1301], '(15Campiani': [1194], 'Morelli': [1196, 1460], 'Fabbrini': [1198, 1462], 'M.': [1199, 1463, 4169], 'Nacci': [1200, 1464], 'V.': [1201, 1465], 'Greco': [1202, 1466], 'Novellino': [1204, 1468], 'Ramunno': [1206, 1470], 'Maga': [1208, 1472], 'Caliendo': [1212, 1476], 'Bergamini': [1214, 1478], 'Faggioli': [1216, 1480], 'F.': [1217, 1221, 1481, 1485, 4171], 'Uccella': [1218, 1482], 'Bolacchi': [1220, 1484], 'Marini': [1222, 1486], '42:': [1228, 1492], '4462-4470Crossref': [1229, 1493], '(45)': [1232, 1496], 'present': [1237], 'work,': [1238], 'mechanism': [1243, 1289], '(−)-': [1248], '(+)-enantiomers': [1250], 'recombinant': [1255], 'isolates,': [1260], 'bearing': [1265], 'mutation.': [1268], 'Our': [1269], 'show': [1271], 'only': [1273, 3120, 3173, 3228], '(−)-enantiomer': [1275], 'retained': [1279], 'full': [1280, 2283], 'antienzymatic': [1281], 'activity,': [1284], 'acting': [1285], 'through': [1286, 4325], 'NNRTIs.': [1294], 'make': [1298], 'synthesis': [1305], 'compounds.': [1311], 'Melting': [1312], 'points': [1313], 'using': [1316, 1748, 1816, 2017, 2296, 3880, 3941, 3996, 4197], 'Buchi': [1318], 'melting': [1319], 'point': [1320, 2860, 4148], 'B-540': [1321], 'apparatus': [1322], 'uncorrected.': [1325], 'IR': [1326, 2038], 'spectra': [1327, 1341, 1529], 'taken': [1329, 1995], 'PerkinElmer': [1331, 1443, 1505], 'Life': [1332, 1444, 1506], 'Sciences': [1333, 1445, 1507], '398': [1334], 'FT': [1336], '1600': [1337], 'spectrophotometers.': [1338], '1H': [1339, 1848, 2042], 'NMR': [1340, 1849, 2043], 'recorded': [1343], 'Bruker': [1346], '200-MHz': [1347, 1354], 'spectrometer': [1348, 1355, 1537, 1577], 'Gemini': [1352], 'Varian': [1353], 'TMS': [1357], 'internal': [1359], 'standard;': [1360], 'values': [1362, 2902, 3083, 3292, 3310, 3440, 3473, 3687, 3709, 3732, 3807, 4124, 4131], 'shifts': [1366], '(δ)': [1367], 'ppm,': [1371], 'coupling': [1373], 'constant': [1374, 2946, 3030, 3329, 3370, 3416, 3458], '(J)': [1375], 'Hz.': [1379], 'reactions': [1381], 'carried': [1383, 2280, 2874], 'out': [1384, 2281, 2875], 'argon': [1387], 'atmosphere.': [1388], 'TLCs': [1389], 'performed': [1391, 1502, 2669, 2890, 4196], 'silica': [1393, 1399, 1647, 1703], 'gel': [1394, 1400], 'plates': [1395], '(Riedel-de-Haen;': [1396], 'Art.37341).': [1397], 'Merck': [1398, 2433], '(Kieselgel': [1401], '60)': [1402], 'flash': [1407, 2015], '(230–400-mesh)': [1409], 'column.': [1410], 'Yields': [1411], 'refer': [1412], 'purified': [1414, 2013, 2491], 'products': [1415, 2973], 'optimized.': [1419], 'Organic': [1420], 'extracts': [1421], 'dried': [1423, 1836], 'over': [1424], 'MgSO4,': [1425], 'solvents': [1428], 'removed': [1430, 1988], 'reduced': [1432], 'pressure.': [1433], 'Optical': [1434], 'rotations': [1435], 'measured': [1437, 1531, 2829, 3342, 3429], 'room': [1439, 1977, 1983, 2128, 2484], 'temperature': [1440, 1676, 2893, 3494], 'model': [1446, 1574, 1582, 1601, 3550], '241': [1447], 'polarimeter.': [1448], 'racemic': [1450, 1712], 'PPO294': [1451], 'obtained': [1453, 2114, 2248], 'described': [1455, 2496, 2673, 2831, 2882, 2914, 3246], 'Ref.': [1457, 3521], '15Campiani': [1458], 'Scholar.': [1498, 3534], 'Elemental': [1499], 'analyses': [1500], '240C': [1508], 'elemental': [1509], 'analyzer': [1510], 'CHNS': [1514], 'EA': [1515], '1110': [1516], 'Thermoquest-analyzer': [1517], 'within': [1522], '±0.4%': [1523], 'theoretical': [1526], 'values.': [1527, 3953], 'Mass': [1528], 'double': [1534], 'focusing': [1535], 'mass': [1536, 1576], 'VG': [1538], '70–250S': [1539], '(VG': [1540], 'Analytical': [1541], 'Ltd.,': [1542], 'Manchester,': [1543], 'UK)': [1544], 'electron': [1546], 'ionization': [1547], 'conditions': [1548, 2672, 2881, 3095, 3266], '(70': [1549], 'eV': [1550], 'accelerating': [1552], 'voltage': [1553], '8': [1555, 3609], 'KV)': [1556], 'Waters': [1560, 1573, 1602], 'Platform': [1561], 'LC': [1562], 'Micromass': [1563], 'spectrometer.': [1564], 'semipreparative': [1571, 1624, 1740], 'HPLC': [1572, 1612, 1815], '600': [1575], 'equipped': [1578], 'Rheodyne': [1581], '7125': [1583], 'injector': [1584], 'valve': [1585], '200-μl': [1588], 'fixed': [1589, 3678, 3875], 'loop,': [1590], 'UV': [1591, 1618], 'detector': [1592, 1600, 1619], '2487': [1593, 1620], '(Waters': [1594, 1621], 'Chromatography,': [1595], 'Milford,': [1596], 'MA),': [1597], 'RI': [1599], '410.': [1603], 'Purity': [1604], 'enantiomers': [1606, 1766, 1810], 'evaluated': [1608, 1812], 'analytical': [1611, 1681, 1814, 2428], 'Alliance': [1613], '2690': [1614], 'coupled': [1615], 'Chromatography).': [1622], 'chromatographic': [1625, 1682], 'column': [1626, 1631, 1666, 1683, 1688], 'stainless': [1629, 1686], 'steel': [1630, 1687], '(10-μm': [1632], 'particle': [1633], 'size)': [1634], '(250': [1635], '×': [1636, 1692, 1745, 2144, 2146, 4233], '20': [1637, 1744, 2117, 2459, 2465], 'mm': [1638, 1694, 2148, 2460, 2466, 2470, 2578, 2583, 2593, 2757], 'ID)': [1639, 1695], 'packed': [1640, 1696], 'Chiralpak-AD,': [1642, 1698], 'amilose': [1643, 1699], 'carbamate': [1644, 1700], 'supported': [1645, 1701], 'gel,': [1648, 1704], 'purchased': [1649, 1705, 2431], 'from': [1650, 1706, 2023, 2403, 2411, 2432, 3333, 3374, 3420, 3500, 3690, 3694], 'Daicel': [1651], 'Chemical': [1652], 'Industries,': [1653], 'Ltd.': [1654], '(Tokyo,': [1655], 'Japan).': [1656], 'Flow': [1657], 'rate': [1658, 3308], 'mobile': [1660, 1819], 'phase': [1661, 1820], '5': [1663, 2477, 2655, 2768, 3482], 'ml/min.': [1664], 'kept': [1668], 'inside': [1669], 'refrigerating': [1671], 'bath': [1672], 'controlled': [1675], '0': [1678, 1736, 4070], '°C.': [1679, 2559, 2621, 4498], '(5': [1689, 1753, 1947], 'μm': [1690, 2602, 2798], '250': [1691, 1746], '4.6': [1693], 'Merck.': [1707], 'A': [1708, 2130, 2576, 2917, 3455, 3646, 3989, 4445], 'solution': [1709, 1937, 2124], '(20': [1715], 'mg,': [1716, 1790, 1798, 1941, 1956], '0.066': [1717], 'mmol)': [1718, 1943], 'ml': [1721], 'hexanes/ethanol/triethylamine': [1723, 1749], '(95:5:0.1),': [1724], 'after': [1725, 4507], 'filtration': [1726], '0.45-μm': [1729], 'Millipore': [1730], 'Corp.': [1731], 'filter,': [1732], '°C': [1737, 1952, 1970, 2475, 2735, 4278], 'Chiralpak-AD': [1741], '(10': [1742], 'μm,': [1743], 'mm)': [1747], '(95:5:0.1)': [1750], 'eluent': [1752], 'ml/min).': [1754], 'effluent': [1756], 'monitored': [1758, 2697], 'λ': [1760], '=': [1761, 1856, 1863, 1894, 1897, 1902, 1905, 2050, 2057, 2064, 2090, 2167, 2211, 2214, 2217, 2221, 2225, 2228, 2244, 2351, 2353, 2362, 2776, 3272, 3661, 3785, 3886], '304': [1762, 1890], 'nm,': [1763], '(+)-PPO463': [1767, 1788, 1825, 1939, 2390], '(−)-PPO464': [1769, 1829, 2393, 2759], 'eluted': [1770], 'retention': [1772], 'times': [1773], '33.7': [1775], '38.4': [1777], 'min,': [1778, 2478], 'respectively.': [1779, 3027, 3262], 'fractions': [1781], 'collected': [1783, 1834, 2234], 'concentrated': [1785], 'afford': [1787], '(8.7': [1789], '87%,': [1791], '100%': [1792], 'enantiomeric': [1793, 1801], 'excess)': [1794, 1802], '(-)-PPO464': [1796], '(8.9': [1797], '89%,': [1799], '99.3%': [1800], 'colorless': [1804, 2033, 2131], 'liquids.': [1805], 'purity': [1807, 2494], '(1': [1821, 2607, 2777, 2800], 'ml/min)': [1822], '(retention': [1823], 'times:': [1824], 'peak,': [1826, 1830], '8.0': [1827], 'min;': [1828], '8.7': [1831], 'min).': [1832], 'Solutions': [1833], 'vacuum': [1839], 'pump,': [1840], 'since': [1841, 3172, 3201], 'oily': [1843], 'residue': [1844, 1993], 'obtained.': [1846], '(+)-PPO463/(−)-PPO464:': [1847], '(CDCl3)': [1850, 2044], 'δ': [1851, 2045], '1.10': [1852], '(t,': [1853, 2047], '3H,': [1854, 2048], 'J': [1855, 1862, 2049, 2056, 2063], '7.0': [1857, 2051], 'Hz),': [1858, 1865, 2052, 2059, 2067], '2.45': [1859], '(q,': [1860, 2054], '2H,': [1861, 2055], '7.1': [1864, 2058], '6.49': [1866], '(m,': [1867, 1870, 1873, 1876, 1879, 1882, 1885, 2069, 2072, 2075, 2078], '1H),': [1868, 1871, 1877, 1880, 1883, 2076], '7.03': [1869], '7.10–7.30': [1872], '5H),': [1874, 2070], '7.37': [1875], '7.51': [1878], '7.94': [1881, 2074], '8.07': [1884], '1H).': [1886, 2079], 'MS': [1887, 2080], '(EI)': [1888, 2081], 'm/z:': [1889], '(M+).': [1891], '(+)-PPO463:': [1892, 1928], '[α]D22': [1893, 1901], '+56.7': [1895], '(c': [1896, 1904, 2089], '0.56': [1898], '(CH2Cl2));': [1899], '(−)-PPO464:': [1900, 1920], '−56.5': [1903], '0.57': [1906], '(CH2Cl2)).': [1907], 'Anal.': [1908, 2093], 'Calcd.': [1909, 2094], '(C19H16N2O2):': [1911], 'C,': [1912, 1921, 1929, 2103], '74.98;': [1913], 'H,': [1914, 1923, 1931, 2098, 2105], '5.30;': [1915], 'N,': [1916, 1925, 1933, 2100, 2107], '9.20.': [1917], 'Found:': [1918, 2102], '75.40;': [1922], '6.65;': [1924], '8.96;': [1926], '75.07;': [1930], '6.05;': [1932], '9.07.': [1934], 'To': [1935], '(65': [1940], '0.214': [1942, 1957], 'anhydrous': [1945], 'tetrahydrofuran': [1946], 'ml)': [1948], 'cooled': [1949, 2482], '−70': [1951, 1969], 'addedN-bromosuccinimide': [1954], '(38': [1955], 'mmol).': [1958], 'mixture': [1961], 'stirred': [1963], 'vigorously': [1964], '1.5': [1966], 'h': [1967, 1981, 4249, 4461, 4506], 'then': [1972, 2480, 2625, 2714, 2761, 2868, 2911, 3601, 3994, 4067, 4082, 4274], 'gradually': [1974], 'wormed': [1975], 'temperature.': [1978, 2129, 2485], 'After': [1979, 2808, 4247], '16': [1980], 'temperature,': [1984], 'solvent': [1986], 'vacuo,': [1990], 'up': [1996], 'dichloromethane;': [1998], 'organic': [2000], 'layer': [2001], 'washed': [2003, 2643], 'brine,': [2005], 'dried,': [2006, 2658], 'concentrated.': [2008], 'crude': [2010], 'product': [2011], 'dichloromethane/hexane': [2018], '(8:2)': [2019], 'eluent.': [2021], 'Recrystallization': [2022], 'hexane': [2024], 'gave': [2025], '31': [2026], 'mg': [2027, 2118], '(38%)': [2028], '(−)-PPO600': [2031, 2112, 2135, 2384], 'prisms': [2034], '(mp': [2035], '155–156': [2036], '°C).': [2037], '(CHCl3)': [2039], '1654': [2040], 'cm−1;': [2041], '1.08': [2046], '2.42': [2053], '7.04': [2060], '(dd,': [2061], '1H,': [2062], '7.9,': [2065], '4.8': [2066], '7.19': [2068], '7.35–7.43': [2071], '2H),': [2073], '8.04': [2077], 'm/z(%):': [2082], '382/384': [2083], '(M+),': [2084], '248/250': [2085], '(100).': [2086], '[α]22D': [2087], '=−89': [2088], '3.2': [2091], '(CHCl3)).': [2092], '(C19H15BrN2O2):': [2096], 'C,59.55;': [2097], '3.95;': [2099], '7.31.': [2101], '59.37;': [2104], '3.72;': [2106], '7.18.': [2108], 'Single': [2109], 'crystals': [2110], 'dissolving': [2116], 'methanol': [2120], 'concentrate': [2126], 'crystal': [2133], '(C19H15N2BrO2,': [2136], 'molecular': [2137], 'weight': [2138, 2445], '383.2)': [2139], 'approximate': [2141], 'dimensions': [2142], '0.15': [2143, 2147], '0.10': [2145], 'submitted': [2150], 'data': [2153, 2193, 3304, 3447, 3558], 'collection': [2154, 2194], 'Siemens': [2157], 'P4': [2158], 'four-circle': [2159], 'diffractometer': [2160], 'graphite': [2162], 'monochromated': [2163], 'Mo-Kα': [2164], 'radiation': [2165], '(λ': [2166], '0.71069': [2168], 'Å).': [2169], 'Lattice': [2170], 'parameters': [2171], 'least-squares': [2175, 2286], 'refinement': [2176, 2278, 2347], '47': [2178], 'randomly': [2179], 'automatically': [2182], 'centered': [2183], 'reflections.': [2184], 'ω/2θ': [2186, 2250], 'scan': [2187, 2202], 'technique': [2188], '4': [2197, 2741, 3453, 4248], '≤': [2198, 2200], '2Θ': [2199], '50°': [2201], 'range.': [2203], 'Crystal': [2204], 'system:': [2205], 'orthorhombic;': [2206], 'space': [2207], 'group:': [2208], 'P212121;': [2209], '8.111(1),': [2212], 'b': [2213], '13.965(2),': [2215], 'c': [2216], '15.087(2)': [2218], 'Å,': [2219], 'V': [2220], '1708.9(4)': [2222], 'Å3,': [2223], 'Z': [2224], '4,': [2226, 4285], 'Dc': [2227], '1.490': [2229], 'g/cm3.': [2230], '3469': [2231], 'reflections': [2232, 2291], '22': [2236], '°C,': [2237, 2817, 4252], 'which': [2239, 2632, 2774, 3748], '3004': [2240], '(Rint': [2243], '0.07).': [2245], 'Absorption': [2246], 'correction': [2247], 'scans': [2251], 'applied.': [2253], 'structure': [2255], 'solved': [2257, 4112], 'direct': [2259], 'methods': [2260], 'implemented': [2261], 'SHELX-97': [2264, 2298], 'program': [2265, 2299], '(39Sheldrick': [2266, 2300], 'G.M.': [2267, 2301], 'SHELX-97,': [2268, 2302], 'Release': [2269, 2303], '97-2.': [2270, 2304], 'University': [2271, 2305], 'Goettingen,': [2273, 2274, 2307, 2308], 'Germany1997Google': [2275, 2309], 'matrix': [2284], 'anisotropic': [2285], 'F2': [2288], 'all': [2290], 'nonhydrogen': [2293], 'atoms': [2294], 'chiral': [2316], 'center': [2317], 'pyridooxazepine': [2320], 'nucleus': [2321], 'made': [2323], 'refined': [2326], 'Flack': [2327], 'parameter': [2328, 3466, 3810], '(16Flack': [2329], 'H.D.': [2330], 'Acta': [2331], 'Crystallogr.': [2332], 'Sect.': [2333], '1983;': [2335], '39:': [2336], '876-881Crossref': [2337], '(10928)': [2339], 'It': [2342], 'resulted': [2343], 'asS.': [2344], 'final': [2346, 2569, 2738, 2765], 'converged': [2348], 'R1': [2350], '0.078,wR2': [2352], '0.129': [2354], 'I': [2356, 3599, 3649, 3654, 3660, 3784], '>': [2357, 2783, 3163, 3655], '2ςI,': [2358], 'goodness': [2359], 'fit': [2361], '1.02.': [2363], 'Minimum': [2364], 'maximum': [2366], 'height': [2367], 'last': [2369], 'Δρ': [2370], 'map': [2371], '−0.58': [2373], '0.47': [2375], 'eÅ−3.': [2376], 'On': [2377, 4283, 4300], 'basis': [2379], 'stereochemistry': [2382, 2388], 'assigned': [2386], '(i.e.': [2394, 4071, 4086], '(S)-': [2395], '(R)-,': [2397], 'respectively).': [2398], '[3H]dTTP': [2399, 2799], '(40': [2400], 'Ci/mmol)': [2401, 2801], 'Amersham': [2404], 'Pharmacia': [2405, 2440, 2456], 'Biotech,': [2406], 'unlabeled': [2408], 'dNTPs': [2409], 'Roche': [2412], 'Molecular': [2413], 'Biochemicals.': [2414], 'Whatman': [2415], 'supplier': [2418], 'GF/C': [2421, 2628, 2823], 'filters.': [2422], 'All': [2423, 3291, 3787], 'reagents': [2425], 'grade': [2429], 'Fluka.': [2435], 'homopolymer': [2437], 'poly(rA)': [2438], '(Amersham': [2439, 2455], 'Biotech)': [2441, 2457], 'mixed': [2443, 3281], 'ratios': [2446], 'nucleotides': [2448], '10:1,': [2450], 'oligomer': [2453], 'oligo(dT)12–18': [2454], 'Tris-HCl': [2461], '(pH': [2462], '8.0),': [2463], 'containing': [2464, 2791, 4263, 4295], 'KCl': [2467], 'EDTA,': [2471], 'heated': [2472], '65': [2474], 'slowly': [2481], 'Recombinant': [2486], 'expressed': [2489, 4158], '>95%': [2493], '(21Ren': [2497], 'Milton': [2499], 'Weaver': [2501], 'K.L.': [2502], 'Short': [2503], 'S.A.': [2504], 'D.I.': [2506], 'D.K.': [2508], 'Fold': [2510], 'Des.': [2511], '8:': [2513], '1089-1094Abstract': [2514], 'Full': [2515, 2517], 'Text': [2516, 2518], 'PDF': [2519], '(277)': [2521], 'had': [2525], 'poly(rA)/oligo(dT)': [2530, 2688], '(see': [2531, 2915], 'below)': [2532], '75,670': [2534], 'units/mg;': [2535], 'unit': [2537], 'polymerase': [2540, 2562, 2680, 2838], 'corresponds': [2542], 'incorporation': [2545], 'nmol': [2548], 'dNMP': [2550], 'acid-precipitable': [2552, 2660, 2826], 'material': [2553], '60': [2555], 'min': [2556, 2618, 2656, 2732, 2812], '37': [2558, 2620, 2734, 2816, 4251, 4277], 'RNA-dependent': [2560, 2678, 2836], 'assayed': [2565, 4309], 'follows;': [2567], 'volume': [2570, 2739, 2766], '25': [2572], 'μl': [2573, 2742, 2787], 'contained': [2574], 'buffer': [2575], '(50': [2577], 'Tris-HCl,': [2579], 'pH': [2580], '7.5,': [2581], 'DTT,': [2584], '0.2': [2585], 'mg/ml': [2586], 'bovine': [2587], 'serum': [2588], 'albumin,': [2589], '4%': [2590], 'glycerol),': [2591], '10': [2592, 2605, 2617, 2756, 2794, 2797, 2811, 3999], 'MgCl2,': [2594], '0.5': [2595], 'μg': [2596], 'poly(rA)/oligo(dT)10:1': [2598], '(corresponding': [2599], '0.3': [2601], '3′-OH': [2603], 'ends),': [2604], 'μm[3H]dTTP': [2606], 'Ci/mmol),': [2608], '2–4': [2610], 'nm': [2611], 'RT.': [2612], 'Reactions': [2613, 2667, 2872], 'incubated': [2615, 2729, 4275], '20-μl': [2622], 'aliquots': [2623, 2819], 'spotted': [2626, 2821], 'glass': [2629], 'fiber': [2630], 'filters,': [2631, 2824], 'immediately': [2634], 'immersed': [2635], '5%': [2637, 2646, 4281], 'ice-cold': [2638, 2647], 'trichloroacetic': [2639, 2648], 'acid.': [2640], 'Filters': [2641], 'twice': [2644], 'once': [2651], 'ethanol': [2653], 'radioactivity': [2661, 2827], 'quantitated': [2663], 'scintillation': [2665], 'counting.': [2666], 'assay.': [2682, 2840], 'Incorporation': [2683], 'radioactive': [2685], 'dTTP': [2686, 2854], 'concentrations': [2691, 3355, 3387, 3615, 3636], 'dNTP': [2695, 2951, 3054, 3102, 3223], 'presence': [2700, 2745, 4344], 'increasing': [2702], 'amounts': [2703], 'indicated': [2707], 'figure': [2710], 'legends.': [2711], 'Data': [2712], 'plotted': [2715, 2869, 3940], 'according': [2716, 3313, 3476, 3519, 3603, 3665], 'Dixon.': [2718], '(20–40': [2721], 'nm),': [2722], 'mutated,': [2727], '2': [2731, 3361, 4039, 4232], 'poly(rA)/oligo(dT),': [2747], '15': [2750], 'nm3′-OH': [2751], 'ends,': [2752], 'Buffer': [2753, 2792], 'A,': [2754, 2793, 2931], 'MgCl2.': [2758], 'added': [2762, 2803], 'μl,': [2769], 'concentration': [2772], '[E:I]/[E0]': [2775], '−': [2778], '1/(1': [2779], '+': [2780, 3628, 3699], '[I]/Ki': [2781], '))': [2782], '0.9.': [2784], 'Then': [2785], '145': [2786], 'mix': [2790], 'mmMgCl2,': [2795], 'points.': [2807], 'additional': [2810], 'incubation': [2814], '50-μl': [2818], 'quantity': [2842], '(v0': [2843], '−vt': [2844], ')/v0,': [2845], 'representing': [2846], 'normalized': [2848], 'difference': [2849], 'between': [2850, 3036, 3540], 'amount': [2852], 'incorporated': [2855], 'zero': [2858], 'points,': [2866], 'time.': [2871, 3462], 'temperatures': [2878, 2909], 'inhibition': [2885, 2905, 3156, 3166, 3197, 3383, 3399, 3403, 3621, 3642, 3906], 'assays.': [2886], 'Separate': [2887], 'incubations': [2888], 'each': [2892, 2990, 3638, 3734, 3756, 3801, 3809, 3866, 4241, 4306, 4322, 4454], 'HAAKE': [2896], 'E8': [2897], 'thermostated': [2898], 'water': [2899], 'bath.': [2900], 'Ki': [2901, 3322, 3350, 3409], 'calculated': [2912, 3294, 3312, 3499, 3602, 3689], 'below).': [2916], 'pathway': [2920], 'assumed': [2922, 2983, 3072, 3546], 'RT-catalyzed': [2925], 'As': [2927], 'SchemeFS1': [2930], 'follows': [2933], 'ordered': [2935], 'bireactant': [2936], 'mechanism,': [2937], 'where': [2938, 3321, 3362, 3394, 3454, 3483, 3563, 3610, 4000], 'TP': [2939, 3052, 3105, 3220], 'binds': [2940], 'equilibrium': [2944, 2956, 3018, 3029, 3116, 3144, 3249, 3327, 3368, 3414], 'dissociation': [2945, 3019, 3040, 3250, 3328, 3369, 3415], 'Km': [2947, 3065, 3078, 3081], '(TP),': [2948], 'followed': [2949], 'constantKm': [2957], '(dNTP),': [2958], 'form': [2960, 3742], 'catalytically': [2962], 'competent': [2963], 'ternary': [2964, 3000, 3135, 3234, 3335, 3376, 3422], 'complex': [2965, 2997, 3001, 3176, 3189, 3336, 3377, 3423], 'reacts': [2967], 'substrate': [2970, 3345, 3354, 3380, 3386, 3432], 'give': [2972], 'RT·P': [2974], 'overall': [2977], 'ratekcat.': [2979], 'NNRTI': [2980], 'possible': [2986], 'principle': [2988], 'intermediate:': [2992], 'free': [2993, 3130], '(RT),': [2995], 'binary': [2996, 3230], '(RT·TP),': [2998], '(RT·TP·dNTP).': [3002], 'formation': [3004], 'RT·I,': [3010], 'RT·TP·I,': [3011], 'RT·TP·dNTP·I': [3013, 3175, 3260], 'driven': [3015, 3140], 'constants': [3020, 3049, 3145], 'Kd': [3021, 3023, 3046, 3146, 3151, 3161, 3164, 3195, 3254, 3273, 3277, 3286, 3363], '(E),': [3022], '(bin),': [3024], 'andKd': [3025, 3148], '(ter),': [3026, 3154, 3165, 3196, 3274, 3280, 3287], 'Each': [3028], 'defined': [3032, 3063], 'ratio': [3035, 3680], 'association': [3042], 'rates,': [3043], '=koff/kon.': [3047], 'Binding': [3048], 'RT·I': [3058, 3188], 'RT·I·TP': [3060], '′(TP)': [3066], 'andKm': [3067], '′(dNTP),': [3068], 'respectively,': [3069], 'equal': [3075, 4132], '(TP)': [3079], '(dNTP)': [3082], 'uninhibited': [3086], 'complexes.': [3087], 'Scheme': [3088, 3340, 3427], 'FS1': [3089, 3107, 3225], 'B': [3090], 'illustrates': [3091], 'experimentally': [3093], 'studies.': [3099], 'With': [3100], 'saturating': [3101, 3219], 'variable': [3104, 3222], '(Scheme': [3106, 3224], 'B,': [3108], 'right': [3109], 'part),': [3110, 3227], 'assumption': [3113], 'rapid': [3115], 'dNTP,': [3119], 'two': [3121, 3674, 4077], 'enzymatic': [3122], 'exist': [3124, 3237], 'steady': [3127, 3240], 'state:': [3128], 'complex.': [3136], 'Inhibitor': [3137, 3242], '(E)': [3147, 3152, 3162, 3193], '(ter).': [3149], 'When': [3150], '=Kd': [3153], 'fully': [3158, 3199, 3288], 'noncompetitive;': [3159], 'uncompetitive': [3168, 3289, 3318], 'low': [3170], '[I],': [3171, 3184], 'formed,': [3179], 'becoming': [3180], 'mixed-noncompetitive': [3181], 'higher': [3183], 'formed.': [3191], 'WhenKd': [3192], '≫': [3194, 3285], 'uncompetitive,': [3200], 'degree': [3209], 'saturation': [3211], 'Similarly,': [3217, 4032], 'B,left': [3226], 'RT·TP': [3231], 'RT·TP·dNTP': [3235], 'state.': [3241], 'constantsKd': [3251], '(bin)': [3252, 3271, 3278, 3284], '(ter)': [3255, 3364], 'RT·TP·I': [3258], 'complexes,': [3261], 'Also,': [3263], 'following': [3268], 'relationships': [3269], 'hold:Kd': [3270], 'inhibition;': [3276], '>Kd': [3279], 'inhibition;Kd': [3283], 'inhibition.': [3290], 'nonlinear': [3296], 'least': [3297], 'computer': [3299], 'fitting': [3300, 3444, 3555], 'experimental': [3303, 3446, 3557], 'appropriate': [3307, 3754, 4297], 'equations.Ki': [3309], 'equation': [3316, 3947], 'inhibition,v=Vm/((Km/[S])+(1+[I]/Ki(obs)))Eq.': [3319], '(obs)': [3323, 3351, 3410], 'apparent': [3326, 3413], 'FS1,': [3341, 3428], 'concentrations.': [3346, 3433], 'Dependence': [3347], 'fitted': [3357, 3389], 'equation,Ki(obs)=(1+(Km/[S]))Kd(ter)Eq.': [3360], 'true': [3367], 'infinite': [3379, 3405], 'concentration.': [3381, 4271, 4299], 'Dose-dependent': [3382], 'equation,E=(Emax([I]/Ki(obs))m)/(1+(Ki(obs)/[I]m)Eq.': [3392], '3': [3393], 'E': [3395, 3564], 'observed': [3398, 3567], '(percentage),Emax': [3400], 'concentration,': [3407, 3589], 'For': [3434, 3463, 3671], 'determination': [3435], 'kinetics,kapp': [3439], 'exponential': [3451], 'equation,(v0−vt)/v0=A(1−e(−kappt))Eq.': [3452], 't': [3460], 'thermodynamic': [3465], 'calculations,': [3467], 'ΔH': [3468], '[ter:I]': [3469, 3472, 3497], 'ΔS': [3471], "van't": [3479], 'Hoff': [3480], 'equation,ln(1/Ki(obs))=−ΔH[ter:I]/RT+ΔS[ter:I]/REq.': [3481], 'R': [3484], 'gas': [3487], 'constant,': [3488], 'T': [3490], '(Kelvin).': [3495], 'ΔG': [3496], 'equation,ΔG[ter:I]=ΔH[ter:I]−TΔS[ter:I]Eq.': [3502], '6': [3503], 'Two': [3504], 'approaches': [3506], 'employed.': [3508], 'method': [3511, 3860, 4202], 'based': [3513, 3792, 3818], 'Lowe': [3516, 3668, 3745], 'additivity': [3517, 3669, 3746], 'model,': [3518], '17Greco': [3522], 'W.R.': [3523, 3760], 'Bravo': [3524, 3761], 'Parsons': [3526, 3763], '47:': [3531, 3768], '331-385PubMed': [3532, 3769], 'Dose-response': [3535], 'curves': [3536, 3864], 'interaction': [3539, 3597, 3723, 3779], 'AZTTP,': [3541], 'follow': [3548], "Hill's": [3549], 'generated': [3553], 'equation,E=(Econ([I]/D50)m)/(1+(D50/[I])m)Eq.': [3561], '7': [3562, 3752], '(percentage': [3569], 'activity),': [3571], 'Econ': [3572], 'control': [3575, 4334], '(activity': [3577], 'absence': [3580], 'inhibitor),': [3583], 'D50': [3584, 3729], '50%': [3587, 3620, 3641, 3902, 3905, 4010, 4026, 4045, 4160, 4315], 'm': [3591, 3731, 3925, 3951], 'sigmoidicity': [3594, 3931], 'parameter.': [3595], 'index': [3598], 'Berenbaum': [3605], 'equation,I=D(1)/D50(1)+D(2)/D50(2)Eq.': [3608], 'D1': [3611, 3627, 3685, 3703], 'D2are': [3613], 'giving': [3619, 3640], 'D2,': [3629, 3707], 'D50(1)': [3631], 'D50(2)': [3633], 'individually.': [3645], 'value': [3647, 3692, 4331], '<': [3650], 'indicates': [3652, 3657, 3663], 'synergy,': [3653, 4123], 'antagonism,': [3658, 4129], 'additivity,': [3664], 'model.': [3670], 'molar': [3679], '(R=': [3681], '[drug': [3682], '1]/[drug': [3683], '2]),': [3684], 'andD2': [3686], 'theD50': [3691], 'derived': [3693, 3725], 'Equation': [3695, 3751], '7,': [3696, 4302], '(D1': [3698], 'D2)': [3700], '=D50': [3701], '=RD2.': [3704], 'Expected': [3705], 'D1,': [3706], 'andDi': [3708], 'i': [3714], 'null': [3718, 3774], 'reference': [3719, 3775], 'hypothesis': [3720, 3776], 'no': [3722, 3778], 'inserting': [3727], 'estimated': [3728], 'equation,': [3747], 'assumes': [3749], 'individually': [3758], '(17Greco': [3759], 'Scholar).1=D1D50(1)EEcon−E1/m1+D2D50(2)EEcon−E1/m2+…+DiD50(i)EEcon−E1/miEq.': [3771], '9': [3772], '(Equation': [3780], '9)': [3781], 'corresponded': [3782], '1.': [3786], 'analysis': [3790, 3824, 4327], 'three': [3797, 4092], 'independent': [3798, 3985, 4106], 'experiments': [3799], 'combination,': [3803], 'S.D.': [3806], 'estimate': [3811], 'indicated.': [3813], 'approach': [3816], 'multiple': [3821], 'Chou': [3826], 'Talalay': [3828, 3831, 3846], '(18Chou': [3829], 'T.C.': [3830, 3845], 'P.': [3832, 3847], 'Eur.': [3833], '1981;': [3836], '115:': [3837], '207-216Crossref': [3838], '(361)': [3841], '19Chou': [3844], 'Adv.': [3848], 'Enzyme': [3849], 'Regul.': [3850], '1984;': [3851], '22:': [3852, 4186], '27-55Crossref': [3853], '(6118)': [3856], 'This': [3859], 'involves': [3861], 'plotting': [3862], 'dose-effect': [3863, 3934, 3937, 3960, 4326], 'agent': [3867, 4005, 4020, 4038], 'multiply': [3873], 'diluted,': [3874], 'agents': [3879, 3968, 4063, 4100], '“median': [3882], 'effect”': [3883], 'equation:fa': [3884], '/fu': [3885], '(D/Dm': [3887], ')m': [3888], '.': [3889], 'equation,D': [3892], 'dose,': [3895], 'Dm': [3896], 'dose': [3899, 3917, 4003, 4017, 4036, 4052, 4164, 4317], 'required': [3900, 4007, 4021, 4040, 4053, 4269], '(e.g.': [3904, 3973, 3983], 'replication),': [3909], 'fa': [3910], 'fraction': [3913, 3922], 'affected': [3914], 'D,': [3918], 'fu': [3919], 'unaffected,': [3923], 'coefficient': [3928], 'signifying': [3929], 'curve.': [3935], 'logarithmic': [3943], 'conversion': [3944], 'determines': [3949], 'andDm': [3952], 'Based': [3954], 'slope': [3957], 'curves,': [3961], 'it': [3962, 4095], 'decided': [3965], 'whether': [3966, 4098], 'mutually': [3970, 3980, 4065, 4080], 'exclusive': [3971], 'action)': [3978], 'nonexclusive': [3981], 'action).': [3988], '“combination': [3990], 'index”': [3991], '(CI)': [3992], 'equation,CI=(D)1/(D50(1))+(D)2/(D50(2))+α(D)1(D)2/(D50(1))(D50(2))Eq.': [3998], '(D50(1)represents': [4001], 'produce': [4009, 4023, 4042, 4055], 'alone,': [4012, 4047], '(D)1': [4014], '(D)2.': [4031], '(D50(2)': [4033], '(D)2': [4049], 'combination.': [4060], 'If': [4061, 4094], 'exclusive,': [4066], 'α': [4068, 4083], 'CI': [4072, 4087, 4118], 'sum': [4075, 4090], 'terms);': [4078], 'nonexclusive,': [4081], 'terms).': [4093], 'uncertain': [4097], 'manner,': [4107], 'formula': [4109], 'ways.': [4115], 'Values': [4116], 'indicate': [4122, 4128, 4135], 'greater': [4125], 'additive': [4136], 'effect.': [4137], 'infectivity': [4139], 'titer': [4140], 'HIV': [4142, 4209], 'isolates': [4143], 'end': [4147, 4501], 'titration': [4149, 4356], 'peripheral': [4151, 4235], 'blood': [4152, 4236, 4481], 'mononuclear': [4153, 4237], 'culture': [4155, 4162], 'supernatants': [4156], 'tissue': [4161], 'infective': [4163], '(TCID50)': [4165], '(37Cattaneo': [4166], 'Zavattoni': [4168], 'Baldanti': [4170], 'Sarasini': [4172], 'Caselli': [4174], 'Maccabruni': [4176], 'Martegani': [4178], 'Torre': [4180], 'Gerna': [4182], 'Microbiologica.': [4184], '281-291PubMed': [4187], 'vitro': [4191], 'susceptibility': [4193], 'assays': [4194], 'modified': [4199], 'ACTG/AIDS': [4200], 'consensus': [4201], '(38Masters': [4203], 'ACTG': [4205], 'Virology': [4206], 'Manual': [4207], 'Laboratories.': [4210], 'National': [4211, 4441], 'Institutes': [4212], 'Health,': [4214], 'Bethesda,': [4215], 'MD1994:': [4216], '1-12Google': [4217], 'Briefly,': [4219], 'day': [4221, 4284, 4301], '0,': [4222], '2000': [4223], 'TCID50': [4224], 'stock': [4227], 'supernatant': [4228, 4256, 4289, 4304], 'inoculated': [4230], '105': [4234], 'cells': [4238], 'growing': [4239], '96-well': [4245], 'plate.': [4246], 'half': [4253, 4286], 'discarded': [4258], 'replaced': [4260, 4291], 'medium': [4262, 4294], 'achieve': [4267], 'Plates': [4272], 'CO2atmosphere.': [4282], 'fresh': [4293], 'p24': [4311, 4330], 'antigen': [4312], 'production.': [4313], '(ID50)': [4318], 'wells': [4335, 4341], '(without': [4336], 'drug)': [4337], 'drugs.': [4347], 'parallel,': [4349], 'toxicity': [4351], 'controls': [4352], 'back': [4354], 'performed.': [4358], 'Disposition': [4359], 'done': [4362], 'male': [4364], 'CD1': [4365], 'CD-COBS': [4368], 'weighing': [4370], '30': [4372], '300': [4374], 'g,': [4375], 'respectively': [4376], '(Charles': [4377], 'River).': [4378], 'Procedures': [4379], 'involving': [4380], 'animals': [4381], 'care': [4384], 'conducted': [4386], 'conformity': [4388], 'institutional': [4391], 'guidelines': [4392], 'compliance': [4396], 'national': [4398], '(D.L.': [4399], 'n.': [4400], '116,': [4401], 'G.U.,': [4402, 4411], '40,': [4404], '18': [4405], 'February': [4406], '1992,': [4407], 'Circolare': [4408], 'No.': [4409], '8,': [4410], '14': [4412], 'July': [4413], '1994)': [4414], 'international': [4416], 'laws': [4417], 'policies': [4419], '(EEC': [4420], 'Council': [4421], 'Directive': [4422], '86/609,': [4423], 'OJ': [4424], 'L': [4425], '358,1,': [4426], 'December': [4427], '12,': [4428], '1987;': [4429], 'Guide': [4430], 'Care': [4433], 'Use': [4435], 'Laboratory': [4437], 'Animals,': [4438], 'United': [4439], 'States': [4440], 'Research': [4442], 'Council,': [4443], '1996).': [4444], 'chronic': [4446], 'jugular': [4447], 'cannula': [4448], '(PE-50': [4449], 'tubing)': [4450], 'implanted': [4452], 'rat': [4455], 'chloral': [4457], 'hydrate': [4458], 'anesthesia': [4459], '24': [4460], 'before': [4462], 'study': [4464, 4504], 'started.': [4465], 'Rats': [4466], 'subcutaneously': [4471], 'orally': [4473], 'PEG-400/ethanol/Tween': [4475], '80': [4476], '(60:30:10,': [4477], 'v/v/v),': [4478], 'serial': [4480], 'samples': [4482], 'drawn': [4484], 'various': [4486], 'times.': [4487], 'Samples': [4488], 'centrifuged,': [4490], 'stored': [4495], '−20': [4497], 'At': [4499], '(4': [4505], 'dosing),': [4508], 'killed': [4511], 'decapitation': [4513], 'deep': [4515], 'anesthesia,': [4516], 'brains': [4518], 'rapidly': [4520], 'removed,': [4521], 'blot': [4522]}, 'cited_by_api_url': 'https://api.openalex.org/works?filter=cites:W2161301173', 'counts_by_year': [{'year': 2016, 'cited_by_count': 1}], 'updated_date': '2024-12-10T02:39:54.464554', 'created_date': '2016-06-24'}
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