Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends.
The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44, West Culture Road, 250012, Jinan, Shandong, P. R. China.
Peng
P
Zhan
Rega Institute for Medical Research, Katholieke Universiteit Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Christophe
C
Pannecouque
Rega Institute for Medical Research, Katholieke Universiteit Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Erik
E
De Clercq
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44, West Culture Road, 250012, Jinan, Shandong, P. R. China.
Xinyong
X
Liu
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000639:trends; D018890:Chemoprevention / Q000379:methods; D015195:Drug Design; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D011355:Prodrugs / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011355:Prodrugs