Developing novel nonnucleoside HIV-1 reverse transcriptase inhibitors: beyond the butterfly.
To date three nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been approved by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus type 1 infection. A limiting factor in the effectiveness of these agents is the development of resistance, manifested by amino acid substitutions within the virally encoded reverse transcriptase (RT). Understanding the mechanism of action of these agents and how resistance develops have broadened the field of NNRTI research to elucidate structural and biochemical features of inhibition in hopes of creating better inhibitors. In this review, the history of NNRTIs will preface the many studies characterizing inhibition and the development of a new paradigm for understanding the molecular mechanism of drug resistance to NNRTIs. Combination therapies including nonnucleoside inhibitors will be discussed, concluding with remarks on potential new inhibitors.
Basavapathruni
Aravind
A
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Anderson
Karen S
KS
D019380:Anti-HIV Agents / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase