Molecular Basis for Drug Resistance in HIV-1 Protease

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.

Keywords: HIV-1 protease; drug resistance; protease inhibitors; structure based drug design; substrate envelope.

Figure 1.

FDA-approved HIV-1 protease inhibitors.

Figure 2.

The scissile bond in polyprotein substrate is hydrolyzed by protease through the transition state intermediate (substrate amino acid residues are marked as...P3, P2, P1, P1′, P2′, P3′…and the corresponding enzyme binding sites as…S3, S2, S1, S1′, S2′, S3′…). Transition state mimics I–V used in the design of currently approved drugs.

Figure 3.

(A) Substrate envelope of HIV protease. PyMOL model generated from overlapping van der Waals volume of substrate peptides. Red: matrix capsid, green: capsid-p2, blue: p2-nucleocapsid, cyan: p1–p6, magenta: reverse transcriptase-ribonucleaseH, yellow: ribnucleaseH-integrase. (B) The inhibitor envelope in red, within the active site of HIV-1 protease, calculated from overlapping van der Waals volume of five or more of eight inhibitor complexes. (C) Superimposition of the substrate consensus volume (blue) with the inhibitor consensus volume (red). Residues that contact with the inhibitors where the inhibitors extend beyond the substrate volume and confer drug resistance when they mutate are labeled (Figures 3A–C, modified from King et al. [38]).

Figure 4.

HIV-1 protease is a homodimer with the catalytic active site formed at the dimeric interface. The majority of residues that differ between various HIV-1 clades map to positions that are outside the active site. Red spheres represent amino acid positions and are indicated only on one monomer for clarity.