The Francis Crick Institute
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HIV-1 integrase inhibitors with modifications that affect their potencies against drug resistant integrase mutants.

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journal contribution
posted on 2021-06-16, 10:24 authored by Steven J Smith, Xue Zhi Zhao, Dario Oliveira Passos, Valerie E Pye, Peter Cherepanov, Dmitry Lyumkis, Terrence R Jr Burke, Stephen H Hughes
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.


Crick (Grant ID: 10061, Grant title: Cherepanov FC001061)