Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise

Area of Science:

• Drug Discovery and Development
• Virology
• Structural Biology

Background:

• HIV-1 reverse transcriptase (RT) is a critical target for antiretroviral therapy.
• Emergence of drug-resistant HIV variants necessitates the development of novel RT inhibitors.
• Catechol diether compounds have shown high potency against wild-type HIV-1 RT.

Purpose of the Study:

• To evaluate the efficacy of novel catechol diether compounds against HIV-1 RT variants with resistance mutations.
• To investigate the structural basis for resistance and retained potency.

Main Methods:

• Screening of catechol diether compounds against HIV-1 clinical isolates.
• Genetic sequencing to identify resistance mutations.
• X-ray crystallography to determine inhibitor-bound RT structures.

Main Results:

• An HIV-1 isolate initially identified as Y181C single mutant was found to possess a V106A/Y181C double mutation.
• Both indolizine and naphthalene catechol diethers inhibited the Y181C single mutant.
• Naphthalene derivatives maintained potency against the V106A/Y181C double mutant, while indolizine derivatives showed reduced efficacy.
• Crystal structures revealed that the naphthyl group's interactions with F227 contribute to potency against the double mutant.

Conclusions:

• The V106A mutation confers increased resistance to catechol diether inhibitors, particularly indolizine derivatives.
• Naphthalene-substituted catechol diethers demonstrate retained activity against HIV-1 RT with the V106A/Y181C double mutation.
• Structural insights explain the differential activity and guide the design of next-generation HIV-1 RT inhibitors.