Abstract
HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. In order to successfully inhibit Gag, understanding of its drug resistance mutations and the elicited structural changes on protease binding needs to be investigated. While mutations on Gag have already been mapped to protease inhibitor resistance, there remain many mutations, particularly the non-cleavage mutations, that are not characterized. Through structural studies to unravel how Gag mutations contributes to protease drug resistance synergistically, it is thus possible to glean insights to design novel Gag inhibitors. In this review, we discuss the structural role of both novel and previously reported Gag mutations in PI resistance, and how new Gag inhibitors can be designed.
Highlights
Many anti-HIV drugs interfere directly with the viral life cycle by targeting key viral enzymes [1], e.g., reverse transcriptase inhibitors [2,3], integrase inhibitors [4,5], and protease inhibitors [6,7]
As Gag is a larger protein than protease, and mutations can contribute to protease inhibitors (PIs) resistance, there is a need to study the mechanisms to how these mutations work
As 2019, Gag 24, is a3243 larger protein than protease, and mutations2 of can contribute to PI resistance, there is a need to study the mechanisms to how these mutations work in synergy with protease
Summary
Many anti-HIV drugs interfere directly with the viral life cycle by targeting key viral enzymes [1], e.g., reverse transcriptase inhibitors [2,3], integrase inhibitors [4,5], and protease inhibitors [6,7]. As Gag is a larger protein than protease, and mutations (both cleavage and non-cleavage) can contribute to PI resistance, there is a need to study the mechanisms to how these mutations work. As 2019, Gag 24, is a3243 larger protein than protease, and mutations (both cleavage and non-cleavage) of can contribute to PI resistance, there is a need to study the mechanisms to how these mutations work in synergy with protease. Such studies will unravel potential weak points to which Gag can be in synergy with protease.
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