Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.
HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.
Sarafianos
Stefan G
SG
Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University, Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA.
Das
Kalyan
K
Hughes
Stephen H
SH
Arnold
Eddy
E
D001665:Binding Sites; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D004351:Drug Resistance / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D054303:HIV Reverse Transcriptase