Abstract
HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.
Highlights
According to the recent reports published by UNAIDS, there are about 33.4 million people living with HIV-AIDS around the globe [1]
Protease inhibitors (PIs) with improved resistance profiles were developed using a solvent anchoring approach [27], and utilizing a new lysine sulfonamide-based molecular core [28]. Another design strategy incorporates substrate envelope constraints into structure-based design and led to the discovery of novel highly potent PIs that are less susceptible to drug-resistance [29]
DRV was developed by both academic and industrial research efforts based on the crystal structures of HIV-1 protease bound to APV, SQV and its analogues bearing the bis-THF moiety at P2 position
Summary
According to the recent reports published by UNAIDS, there are about 33.4 million people living with HIV-AIDS around the globe [1]. (Figure 1): Saquinavir (SQV) [7], Indinavir (IDV) [8], Ritonavir (RTV) [9], Nelfinavir (NFV) [10], Amprenavir (APV) [11], Lopinavir (LPV) [12], Atazanavir (ATV) [13], Tipranavir (TPV) [14], and Darunavir (DRV) [15,16,17] These inhibitors represent the most potent anti-AIDS drugs reported to date and are essential components of the highly active antiretroviral therapy (HAART) [18,19]. PIs with improved resistance profiles were developed using a solvent anchoring approach [27], and utilizing a new lysine sulfonamide-based molecular core [28] Another design strategy incorporates substrate envelope constraints into structure-based design and led to the discovery of novel highly potent PIs that are less susceptible to drug-resistance [29].
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