Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

Abstract

The virally encoded protease is an important drug target for AIDS therapy. Despite the potency of the current drugs, infections with resistant viral strains limit the long-term effectiveness of therapy. Highly resistant variants of HIV protease from clinical isolates have different combinations of about 20 mutations and several orders of magnitude worse binding affinity for clinical inhibitors. Strategies are being explored to inhibit these highly resistant mutants. The existing inhibitors can be modified by introducing groups with the potential to form new interactions with conserved protease residues, and the flexible flaps. Alternative strategies are discussed, including designing inhibitors to bind to the open conformation of the protease dimer, and inhibition of the protease-catalyzed processing of the Gag-Pol precursor.

Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics

“…Analysis of multidrug resistant mutants of HIV PR suggests that up to 20 mutations may be necessary to acquire high levels of resistance to several drugs [10]. The mutations act synergistically to evade inhibitors by different mechanisms.…”

Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme

“…However, the short replication cycle of 1–2 days 6 combined with error-prone nature of RT (~2×10 −5 errors/nucleotide per replication cycle) 7 favor rapid evolution of mutations selected under drug pressure thus resulting in extreme drug resistance. 8–11 …”

“…4,8,9,12–14 One well characterized extremely drug resistant isolate of PR bearing 19 mutations (PR20) 10,15–17 exhibits 3–4 orders of magnitude weaker binding to clinical PIs relative to the wild-type enzyme. However, it mediates Gag processing only about 4-fold more slowly and retains the same order of cleavage as the wild-type enzyme.…”

Predicting HIV-1 resistance to protease inhibitors: A new structure-based algorithm exploring binding-site Molecular Interaction Fields dissimilarities

“…[1] Given the ease of quickly and affordably sequence HIV from infected individuals, considerable progress -in the sense of predicting resistance towards drugs -could be made by developing tools to link specific genetic mutations with the resulting structural and chemical alterations in the active site of the target enzymes. [2] In recognition of a serious medical need identified by a team of virologists working at the University of Coimbra teaching Hospital and with the intent of helping rationalize and personalize the choice of anti-HIV therapies, we set out to develop a new computational algorithm to predict resistance to protease inhibitors in HIV-1 via detection of bindingsite Molecular Interaction Fields (MIF) dissimilarities. Briefly, the algorithm works by 1) automatically generating high-quality 3D protein model structures from HIV-1 protease sequences; 2) capturing subtle, mutation-induced, chemical perturbations within the binding sites of resistant and non-resistant HIV-1 protease structures using a MIFbased approach; and 3) quantifying binding site dissimilarities based on MIF analysis, and translating these into a resistance score.…”