Reverse transcriptase inhibitors as microbicides

Current HIV Research

Volumn 10, Issue 1, 2012, Pages 27-35

  Lewi, Paul ^a   Heeres, Jan ^b   Ariën, Kevin ^c   Venkatraj, Muthusamy ^d   Joossens, Jurgen ^d   van der Veken, Pieter ^d   Augustyns, Koen ^d   Vanham, Guido ^c,d,e  

^a Institute of Tropical Medicine ^*  (Belgium)

^b University of Antwerp ^*  (Belgium)

^c INSTITUTE OF TROPICAL MEDICINE   (Belgium)

^d UNIVERSITY OF ANTWERP   (Belgium)

^e VRIJE UNIVERSITEIT BRUSSEL   (Belgium)

Author keywords

Gel; HIV; Intravaginal ring; Microbicide; NNRTI; NRTI; NtRTI; Reverse transcriptase

Indexed keywords

CARRAGEENAN; DAPIVIRINE; EMTRICITABINE; ETRAVIRINE; IQP 0528; MC 1220; MICROBICIDE; MIV 150; MIV 160; MIV 170; N [4 CHLORO 3 (3 METHYL 2 BUTENYLOXY)PHENYL] 2 METHYL 3 FURANCARBOTHIOAMIDE; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; PHI 236; PHI 443; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAMPIDINE; TENOFOVIR; TENOFOVIR DISOPROXIL; THIOUREA DERIVATIVE; TROVIRDINE; UNCLASSIFIED DRUG; WHI 07;

ANTIVIRAL ACTIVITY; CELL VIABILITY; CHEMICAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG HALF LIFE; DRUG MEGADOSE; DRUG POTENTIATION; DRUG SAFETY; DRUG TOLERABILITY; EXPLANT; HEALTH CARE ACCESS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 2; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LOWEST INCOME GROUP; NONHUMAN; PATIENT COMPLIANCE; PLASMA HALF LIFE; RETROVIRUS INFECTION; REVIEW; SIMIAN IMMUNODEFICIENCY VIRUS; UNSPECIFIED SIDE EFFECT; VIRUS REPLICATION; VIRUS TRANSMISSION;

EID: 84857133613     PISSN: 1570162X     EISSN: 18734251     Source Type: Journal    
DOI: 10.2174/157016212799304643     Document Type: Review

References (116)

1. Abdool Karim SS, Abdool Karim Q, Antiretroviral prophylaxis: a defining moment in HIV control. Lancet 2011 doi:10.1016/S0140-6736(11)61136-7.
2. Martinez J, Coplan P, Wainberg MA. Is HIV drug resistance a limiting factor in the development of anti-HIV NNRTI and NRTIbased vaginal microbicides? Antiv Res 2006; 71: 343-350.
3. Grant RM, Hamer D, Hope T, et al. Whither or wither microbicides? Science 2008; 321: 532-534.
4. Turpin JA, Topical microbicides to prevent the transmission of HIV: formulation gaps and challenges. Drug Deliv Transl Res 2011; 1: 194-200.
5. Van Rompay KK. Antiretroviral drug studies in nonhuman primates: a valid animal model for innovative drug efficacy and pathogenesis studies. AIDS Rev 2005; 7: 67-83.
6. Van Rompay K. Contributions of nonhuman primate studies to the use of HIV drugs to prevent infection. 2009. http//:speakingofresearch.files.wordpress.com/2009/nhp_prophylaxis_van_rompay.doc. Accessed July 16, 2011.
7. Klasse PJ, Shattock R, Moore JP. Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission. Ann Rev Med 2008; 59: 291-307.
8. th Framework Programme (FP7) of the European Commission, 2010. http://chaarm.eu/partners/partners-profiles-0. Accessed Aug 19, 2011.
9. Das K, Bauman JD, Clark AD Jr, et al. High-resolution structure of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations, PNAS 2008; 105: 1466-1471.
10. De Clercq E. The discovery of antiviral agents: ten different compounds, ten different stories. Medicin Res Rev 2008; 28: 929-953.
11. De Clercq E. The role of tenofovir in the prevention of HIV infections. AIDS 2006; 20: 1990-1991.
12. Herrera C, Cranage M, McGowan I, Anton P, Shattock R. Reverse transcriptase inhibitors as potential colorectal microbicides. Antimicrob Agents Chemotherap 2009; 53: 1797-1807.
13. Garcia-Lerma JG, Otten RA, Qari SH, et al. Prevention of rectal SHIV transmission in macaques by daily intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 2008; 5: e28.
14. Tsai CC, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonomethoxypropyl) adenine. Science 1995; 270: 1197-1198.
15. Cranage M, Sharpe S, Herrera C, et al. Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure of tenofovir gel. PLoS Med 2008; 5: e157.
16. Parikh UM, Dobard C, Sharma S, et al. Complete protection from repeated vaginal SHIV exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine. J Virol 2009; 83: 10358-10365.
17. Denton PW, Estes JD, Sun Z, et al. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 2008; 5: e16.
18. Denton PW, Othieno F, Martinez-Torrez F, et al. One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for validation of microbicide candidates. J Virol 2011; 85: 7582-7593.
19. Mayer KH, Maslanskowski LA, Gai F, et al. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIVinfected and uninfected women. AIDS 2006; 20: 543-551.
20. Schwartz J, Kashuba A, Rezk N, et al. Preliminary results from a pharmacokinetic study of the candidate vaginal microbicide 1% gel tenofovir gel. Microbicides 2008 Conference, New Delhi, India, 2008.
21. Keller MJ, Madan RP, Torres NM, et al. A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following applications of 1% tenofovir gel. PLoS ONE 2011; 6: e16475.
22. Ariën KK, Jespers V, Vanham G. HIV sexual transmission and microbicides. Rev Med Virol 2011; 21:110-133.
23. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. on behalf of the CAPRISA 004 trial group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329:1168-1174.
24. Cates W. After CAPRISA 004: time to re-evaluate the HIV lexicon. Lancet 2010; 376: 495-496.
25. Ariën KK, Vanham G. First real success for anti-HIV gel: a new start for HIV microbicides? Future Microbiol 2010; 5: 1621-1623.
26. Check E. HIV trial doomed by design, say critics. Science 2007; 448: 110-111.
27. WHO/UNAIDS Consensus Meeting. Next steps with 1% tenofovir. Johannesburg, South Africa, 25-26 Aug, 2010.
28. Das K, Arnold E. Crystal structure of HIV-1 Reverse transcriptase in complex with Janssen-R147681. X-ray diffraction study. Protein Data Base, PDB ID 1s6q, 2004.
29. D'Cruz O J, Uckun FM, Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum antihuman immunodeficiency virus microbicide. Mol Hum Reprod 2005; 11: 767-777.
30. D'Cruz OJ, Uckun FM. Dawn of non-nucleoside inhibitor-based anti-HIV microbicides. J Antimicrob Chemother 2006; 57: 411-423.
31. Gali Y, Delezay O, Brouwers J, et al. In vitro evaluation of viability, integrity and inflammation in genital epithelia upon exposure to pharmaceutical excipients and candidate microbicides. Antimicrob Agents Chemother 2010; 54: 5105-5114.
32. Van Herrewege Y, Vanham G, Michiels J, et al. A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides. Antimicrob Agents Chemother 2004; 10: 3684-3689.
33. th Conf Retrovir Opport Inf (CROI) 2005, Boston, MAS. Feb 22-25, 2005.
34. Van Herrewege Y, Michiels J, Waeytens A, et al. A dual chamber model of female cervical mucosa for the study of HIV transmission and for the evaluation of candidate HIV Microbicides. Antiv Res 2007; 74: 111-124.
35. La Colla P. Report on the European 6th Framework Programme. Selection and development of microbicides for mucosal use to prevent sexual HIV transmission/acquisition (SHIVA), June 2007. http://www.edctp.org/fileadmin/documents/Microbicide_Stakeholder_Paolo_La_Colla.pdf. Accessed July 26, 2011.
36. th Conference on Retroviruses and Opportunistic Infections (CROI); Chicago, Ill. Feb 4-8, 2001.
37. Van Roey JM, De Bethune MP, Stoffels P. Microbicidal pyrimidine or triazine compounds for preventing sexual HIV transmission. Patent application WO2003094920, 2003.
38. International Partnership for Microbicides, IPM Clinical trials, 2011. http://www.ipmglobal.org/our-work/research/clinical-trial. Accessed July 15, 2011.
39. Lewi PJ, Arnold E, Andries K, et al. Correlations between factors determining the pharmacokinetics and antiviral activity of HIV-1 nonnucleoside reverse transcriptase inhibitors of the diaryltriazine and diarylpyrimidine classes of compounds. Drugs R D 2004; 5: 247-257.
40. Meldrum J. Microbicides 2004. Report for NAT and global Campaign for Microbicides. Anti-HIV drugs as microbicides, p.19, 2004. http://www.docstoc.com/docs/44696874/Microbicides-2004. Accessed July 21, 2011.
41. Balzarini J, Van Damme L. Microbicide drug candidates to prevent drug infection. Lancet 2007; 369: 787-797.
42. Jespers VA, Van Roey JM, Beets GI, Buvé AM. Dose-ranging phase 1 study of TMC120, a promising vaginal microbicide, in HIV-negative and HIV-positive female volunteers. Acquir Immune Defic Syndr 2007; 44: 154-158.
43. Nel AM, Smythe SC, Habibi S, Kaptur PE, Romano JW. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs hydroxyethylcellulose-based universal placebo gel. J Aquir Immune Defic Syndr 2010; 55: 161-169.
44. Volovik Frenkel Y, Clark AD Jr, Das K, et al. Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability. J Med Chem 2004; 48: 1974-1983.
45. Heeres J, Lewi PJ, The medicinal chemistry of the DATA and DAPY series of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). In: E. De Clercq, Ed. Advances in antiviral drug design. Amsterdam: Elsevier 2007; pp. 213-242.
46. Nuttall JP, Thake DC, Lewis MG, et al. Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C]dapivirine for 7 days. Antimicrob Agents Chemother 2008; 52: 909-914.
47. Malcolm RK, Woolfson AD, Toner C, Morrow RJ, McCullagh SD. Long-term controlled-release of the HIV microbicide TMC120 from silicone elastomer vaginal rings. J Antimicrob Chemother 2005; 56: 954-956.
48. Woolfson AD, Malcolm RK, Morrow RJ, Toner CF, McCullogh SD. Intravaginal ring delivery of the reverse transcriptase inhibitor TMC120 as an HIV microbicide. Int J Pharmaceut 2006; 325: 82-89.
49. Costa L, Aguiar R, Pereira H, Brindeiro R, Tanuri A. Evaluation of nevirapine permeability and retention in HIV-1 cell free and budded virions. 3rd Int AIDS Soc (IAS) Conf on HIV patogenesis and treatment. Rio de Janeiro, Brazil. July 24-27, 2005.
50. Aguiar RS, Costa LJ, Pereira HS, Brindeiro RM, Tanuri A. Development of a new methodology for screening of human immunodeficiency virus type 1 microbicides based on real-time PCR quantification. Antimicrob Agents Chemother 2007; 51: 638-644.
51. Njai HF, Janssen CG, Garcia S, Fransen K, et al. Pre-incubation of cell-free HIV-1 group M isolates with non-nucleoside reverse transcriptase inhibitors blocks subsequent viral replication in cocultures of dendritic cells and T cells. Antivir Ther 2005; 10: 255-262.
52. Van Herrewege Y, Michiels J, Van Roey J, et al. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother 2004; 48: 337-339.
53. Terrazas-Aranda KI, Van Herrewege Y, Lewi PJ, Van Roey J, Vanham G. In vitro pre- and post-exposure prophylaxis using HIVinhibitors as microbicides against cell-free and cell-associated HIV-1 infection. Antivir Chem Chemother 2007; 18: 141-151.
54. Schader SM, Colby-Germinario SP, Schachter JR, Xu H, Wainberg MA. Synergy against drug resistant HIV-1 with the microbicide antiretrovirals, dapivirine and tenofovir, in combination. AIDS 2011; 25: 1585-1594.
55. Harman S, Perumal D, Fletcher P, et al. TMC120 blocks HIV-1 infection in cellular and human cervical tissue models. 3rd IAS Conference on HIV pathogenesis and treatment; Rio de Janeiro, Brazil. July 24-27, 2005.
56. Fletcher P, Harman S, Azijn H, et al. Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside transcriptase inhibitor. Antimicrob Agents Chemother 2009; 53: 487-495.
57. Fletcher PS, Elliot J, Grivel JC, et al. Ex-vivo culture of colorectal tissue for the evaluation of candidate microbicides. AIDS 2006; 20: 1237-1244.
58. Di Fabio S, Van Roey J, Giannini G, et al. Infection of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation. AIDS 2003; 17: 1597-1604.
59. Van 't Klooster, Guzdev B, Horban A, et al. The novel nonnucleoside reverse transcritase inhibitor TMC120 has potent antiretroviral activity after short-term monotherapy in treatment naive, HIV-1 infected subjects. 14th Int. Conference on Antiretroviral Research 2001, April 8-13, Seattle, WA. Antivir Res 2001; 50: A40.
60. Romano J, Variano B, Coplan P, et al. Safety and availability of dapivirine (TMC120) delivered from an intravaginal ring. AIDS Res Hum Retrovir 2009; 25: 483-488.
61. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Aquir Immune Defic Syndr 2009; 51: 416-423.
62. Ren J, Esnouf RM, Hopkins AL, et al. Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives. Biochem 1998; 37: 14394-14403.
63. Barnard J, Borkow G, Parniak MA, The thiocarboxanilide nonnucleoside UC781 is a tight-binding inhibitor of HIV-1 reverse transcriptase. Biochem 1997; 36: 7786-7792.
64. Buckheit RW Jr, Kinjerski TL, Fliakas-Boltz V, et al. Structureactivity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide. Antimicrob Agents Chemother 1995; 39: 2718-2727.
65. Buckheit RW Jr, Snow MJ, Fliakas-Boltz V, et al. Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates. Antimicrob Agents Chemother 1997; 41: 831-837.
66. Balzarini J, Brouwer WG, Felauer EE, De Clercq E, Karlsson A. Activity of various thiocarboxanilide derivatives against wild-type and several mutant immunodeficiency virus type 1 strains. Antimicrob Agents Chemother 1996; 40: 1454-1466.
67. Balzarini J, Naesens L, Verbeken E, et al. Preclinical studies on thiocarboxanilide UC-781 as a virucidal agent. AIDS 1998; 9: 1129-1138.
68. Buckheit RW Jr, Hollingshead M, Stinson S, et al. Efficacy, pharmacokinetics, and in vivo antiviral activity of UC781, a potent, orally bioavailable nonnucleoside reverse transcriptase inhibitor of HIV type 1. AIDS Res Hum Retrovir 1997; 13: 789-796.
69. Goddeeris C, Coacci J, Van den Mooter G. Correlation between digestion of the lipid phase of smedds and release of the anti-HIV drug UC781 and the anti-mycotic drug enilconazole from smedds. Europ J Pharmaceut Biopharmaceut 2007; 66: 173-181.
70. Yang H, Parniak MA, Isaacs CE, Hillier SL, Rohan LC. Characterization of cyclodextrin inclusion complexes of the anti-HIV non-nucleoside reverse transcriptase inhibitor UC781, AAPS J 2008; 10: 606-613.
71. Fletcher P, Kiselyeva Y, Wallace G, et al. The nonnucleoside reverse transcriptase inhibitor UC-781 inhibits human immunodeficiency virus type 1 infection of human cervical tissue and dissemination by migratory cells. J Virol 2005; 79: 11179-11186.
72. Borkow G, Barnard J, Nguyen TM, et al. Chemical barriers to human immunodeficiency virus type 1 (HIV-1) infection: retrovirucidal activity of UC781, a thiocarboxanilide nonnucleoside inhibitor of HIV-1 reverse transcriptase. J Virol 1997; 71: 3023-3030.
73. Hossain MH, Parniak MA. In vitro microbicidal activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 against human immunodeficiency virus type 1. J Virol 2006; 80: 4440-4446.
74. Selhorst P, Vazquez A C, Terrazas-Aranda K, et al. Human immunodeficiency virus type 1 (cross-)resistance to nonnucleoside reverse transcriptase inhibitors currently under development as microbicides. Antimicrob Agents Chemother 2011; 55: 1403-1413.
75. Borkow G, Arion D, Wainberg MA, Parniak MA. The thiocarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of 3'-azido-3'-deoxythymidine (AZT) against AZTresistant human immunodeficiency virus type 1. Antimicrob Agents Chemother; 43: 259-263.
76. Liu S, Lu H, Neurath AR, Jiang S. Combination of candidate microbicides cellulose acetate 1,2-benzenedicarboxylate and UC781 has synergistic and complementary effects against human immunodeficiency virus type 1 infection. Antimicrob Agents Chemotherap 2005; 49: 1830-1836.
77. Watts P, Wallace G, Mahmood N, et al. UC781 blocks localized infection and cell dissemination pathways within human cervical tissue. Proceedings Microbicides 2004, London, March 28-31 2004.
78. Cummins JE Jr, Guarner J, Flowers L, et al. Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. Antimicrob Agents Chemother 2007; 51: 1170-1179.
79. Clark MR, Kiser P F, Laxley A, et al. Pharmacokinetics of UC781-loaded intravaginal ring segements in rabbits, a comparison of polymer matrices. Drug Deliv Translat Res 2007; 1: 238-246.
80. Clark MR, McCormick TJ, Doncel GF, Friend DR. Preclinical evaluation of UC781 microbicide vaginal drug delivery. Drug Deliv Translat Res 2011; 1: 175-182.
81. Patton DL, Cosgrove Sweeney YT, Balkus JE, et al. Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother 2007; 51: 1608-1615.
82. Schwartz JL, Kovalevsky G, Lai JJ, et al. A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor. Sex Transm Dis 2008; 35: 414-419.
83. Cision Wire. Medivir licenses MIV-150 to Population Council. CisionWire, Press Release, July 2003. http://www.cisionwire.com/medivir/r/medivir-licenses-miv-150-to-population-council,c82499. Accessed Aug 15, 2011.
84. Zhang H, Oberg B, Bottiger D, et al. MIV-150 in a vaginal microbicide with superior anti-HIV activities. 15th Int Conf AIDS 2004, Bangkok, Thailand, July 11-16, 2004.
85. Fernandez-Romero JA, Thorn M, Turville SG, et al. Carrageenan/MIV-150 (PC-815), a combination microbicide. Sex Transm Dis 2007; 34: 9-14.
86. Skoler-Karpoff S, Ramjee G, Ahmed K, et al. Efficacy of Carraguard® for prevention of HIV infection among women in South Africa: a randomized, double-blind, placebo controlled trial. Lancet 2008; 372: 1977-1987.
87. Singer R, Derby N, Rodriguez A, et al. An NNRTI MIV-150/carrageenan gel prevents rectal immunodeficiency virus infection in macaques. J Virol 2011; 85: 5504-5512.
88. Turville SG, Aravantinou M, Miller T, et al. Efficacy of Carraguard®-based microbicides in vivo despite variable in vitro activity. PLoS ONE 2008; 3, e3162.
89. Kenney J, Aravantinou M, Singer R, et al. An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques. PLoS One 2011; 6: e15835.
90. Medivir AB. Non-nucleoside reverse transcriptase inhibitors. Example 45, Patent WO02/070516, Sept 2002.
91. Ying H. Medivir transfers HIV drug Alovudine to Beijing Mefuvir. Pharmasia News, Jan 2008. http://fdcalerts.typepad.com/asia/2008/01/medivir-transfer.html. Accessed Aug 15, 2011.
92. Elinder M, Selhorst P, Vanham G, et al. Inhibition of HIV-1 by non-nucleoside reverse transcriptase inhibitors via an induced fit mechanism - Importance of slow dissociation and relaxation rates of antiviral activity. Biochem Pharmacol 2010; 80: 1133-1140.
93. Chen CL, Venkatachalam TK, Waurzyniak B, Chelstrom L, Uckun FM. In vivo toxicity, pharmacokinetic features and tissue distribution of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. Drug Res 2001; 51: 574-581.
94. D'Cruz OJ, Venkatachalam TK, Uckun FM. Novel thiourea compounds as dual-function microbicides. Biol Reprod 2000; 63: 196-205.
95. D'Cruz OJ, Venkatachalam TK, Mao C, Qazi S, Uckun FM. Structural requirements for potent anti-human immunodeficiency virus (HIV) and sperm-immobilizing activities of cyclohexenyl thiourea and urea non-nucleoside inhibitors of HIV-1 reverse transcriptase. Biol Reprod 2002; 67: 1959-1974.
96. D'Cruz OJ, Samuel P and Uckun FM. PHI-443: A novel noncontraceptive broad-spectrum anti-human immunodeficiency virus microbicide. Biol Reprod 2004; 71: 2037-2047.
97. D'Cruz OJ, Uckun FM. Mucosal safety of PHI-443 and stampidine as a combination microbicide to prevent genital transmission of HIV-1. Fertil Steril 2007; 88 (4 Suppl): 1197-1206.
98. D'Cruz OJ, Uckun FM. Microbicides for multi-drug resistant and multitropic HIV-1. Curr Opin Invest Drugs 2008; 9: 152-169.
99. Pani A, Musiu C, Loi AG, et al. DABOs as candidates to prevent mucosal HIV transmission. Antiv Chem Chemother. 2001; 12 (Suppl 1): 51-59.
100. Caron M, Besson G, Etenna SLD, et al. Protective properties of non-nucleoside reverse transcriptase inhibitor (MC1220) incorporated into liposome against intravaginal challenge of rhesus macaques with RT-SHIV. Virol 2010; 405: 225-233.
101. Stolte Leeb N, Loddo R, Antimisiaris S, et al. Topical nonnucleoside reverse transcriptase inhibitor MC1220 partially prevents vaginal RT-SHIV infection of macaques. AIDS Res Hum Retrovir 2011, doi:10.1089/AID.2010.0339.
102. D'Cruz OJ, Uckun FM. Novel derivatives of phenethyl-5-bromopyridylthiourea and dihydroalkoxybenzyl-oxopyrimidine are dual-function spermicides with potent anti-human immunodeficiency virus activity. Biol Repr 1999; 60: 1419-1428.
103. Nuttall JP, Romano J, Douville K, et al. The future of HIV prevention: prospects for an effective anti-HIV microbicide. Infect Dis Clin N Am 2007; 21: 219-239.
104. Buckheit RW, Hartman TL, Watson KM, et al. The structureactivity relationship of 2,4(1H,3H)-pyrimidinedione derivatives as potent HIV type 1 and type 2 inhibitors. Antivir Chem Chemother 2007; 18: 259-275.
105. Buckheit RW Jr, Hartman TL, Watson KM, Chung SG, Cho EH. Comparative evaluation of the inhibitory activation of a series of pyrimidinedione congeners that inhibit human immunodeficiency virus type 1 and type 2. Antimicrob Agents Chemother 2008; 52: 225-236.
106. Buckheit RW, Jr, Development of pyrimidinedione NNRTIs with a high genetic barrier to resistance. http://www.ihlpress.com/pdf20files/hivdart08_presentations/10_buckheit.pdf. Accessed July 26, 2011.
107. Ham A, Watson KM, Yang L, et al. Formulation of IQP-0528 into intravaginal rings as a topical microbicide for the prevention of HIV. Symposium on advancing prevention technologies for sexual and reproductive health, Berkeley CAL, March 24-25, 2009.
108. Mahalingam A, Simmons AP, Ugaonkar SR, et al. Vaginal microbicide gel for the delivery of IQP-0528 a pyrimidinedione analog with a dual mechanism of action against HIV-1. Antimicrob Agents Chemother 2011; 55: 1650-1660.
109. Watson KM, Buckheit CE, Buckheit RW Jr. Comparative evaluation of virus transmission by dual-acting pyrimidinedione microbicides using the microbicide transmission and sterilization assay (MTSA). Antimicrob Agents Chemother 2008; 52: 2787-2796.
110. Ham AS, Rohan LC, Boczar AD, Watson KM, Buckheit RW. Formulation of IQP-0528 into intravaginal films as a topical microbicide for the prevention of HIV. http://www.aapsj.org/abstracts/NBC_2010/NBC-000277.pdf. Accessed July 26, 2011.
111. Srinivasan P, Johnson T, Martin A, et al. Vaginal release kinetics of pyrimidinedione IQP-0258 from a polyurethane intravaginal ring. 28th Annual symposium on nonhuman primate models for AIDS. Prevention - vaccines and microbicide. New Orleans LA, Oct 19-22, 2010.
112. D'Cruz OJ and Uckun FM. Influence of long-term stability conditions on microbicidal prodrug (WHI-07) loaded gelmicroemulsion. AAPS Pharm Sci Tech 2006; 7: E1-E8.
113. D'Cruz OJ, Erbeck D, Uckun FM, Developmental toxiciology studies of WHI-07, a novel nucleoside analogue-based dualfunction microbicide, administered intravaginally to rabbits. Toxicol Pathol 2003; 31: 698-708.
114. D'Cruz OJ, Uckun FM. Preclinical overview of WHI-07, a novel nucleoside analog-based dual-function microbicide. Curr Medicin Chem 2004; 3: 15-29.
115. D'Cruz OJ, Waurzyniak B, Uckun FM. Antiretroviral spermicide WHI-07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats. Antimicrob Agents Chemother 2004; 48: 1082-1088.
116. D'Cruz OJ and Uckun FM. Preclinical evaluation of a dual-acting microbial prodrug WHI-07 in combination with vanadocene dithiocarbamate in the female reproductive tract of rabbit, pig and cat. Toxicol Pathol 2007; 35: 910-927.