HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants.

Steven J Smith,Dmitry Lyumkis,Peter Cherepanov,Stephen H Hughes,Dario Oliveira Passos,Terrence R Burke,Valerie E Pye,Xue Zhi Zhao

doi:10.1021/acsinfecdis.0c00819

Abstract

Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker. The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants. However, because there are mutations that reduce the potency of all of the available INSTIs, new and better compounds are needed. Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3′-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants. We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold. One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested. Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

Highlights

Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS
It is relatively easy for HIV-1 to develop resistance to the first-generation INSTIs RAL and EVG, which share overlapping resistance profiles.[6−10] the second-generation INSTIs, DTG and BIC, retain good activity against common RAL- and EVG-resistant HIV-1 strains, and it appears to be more difficult for the virus to develop resistance to the second generation INSTIs.[11−19] The ability of DTG and BIC to inhibit the replication of many of the RAL- and EVG-resistant mutants seems to be related to their extended tricyclic scaffolds.[19−21]
We explored the structure of these compounds in the context of HIV IN models and discuss how these modifications can be used in the design of nextgeneration INSTIs

Summary

Introduction

Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTI pharmacophore comprises two key elements: a metal chelating scaffold, optimized to bind a pair of Mg2+ ions in the IN active site, and a halobenzyl side chain, connected to the core by a flexible linker, which binds to viral DNA.[4] All of the FDA-approved INSTIs potently inhibit the replication of wildtype (WT) HIV-1. It is relatively easy for HIV-1 to develop resistance to the first-generation INSTIs RAL and EVG, which share overlapping resistance profiles.[6−10] the second-generation INSTIs, DTG and BIC, retain good activity against common RAL- and EVG-resistant HIV-1 strains, and it appears to be more difficult for the virus to develop resistance to the second generation INSTIs.[11−19] The ability of DTG and BIC to inhibit the replication of many of the RAL- and EVG-resistant mutants seems to be related to their extended tricyclic scaffolds.[19−21]

Methods

Results

Conclusion