Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity.

ABSTRACT: HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2'-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PR_WT) and highly-multi-PI-resistance-associated PR_DRV^R_P51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyc

SUBMITTER: Bulut H 

PROVIDER: S-EPMC7326966 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature