AI Article Synopsis
- Allosteric HIV-1 integrase inhibitors (ALLINIs) like KF116 show potential in disrupting viral maturation by causing the integrase enzyme to hyper-multimerize.
- KF116 specifically targets integrase tetramers, which are crucial for HIV replication, leading to effective interference during the virus's infection process.
- The synthesized enantiomer of KF116 demonstrates strong activity against both wild-type HIV-1 and resistant strains, indicating it may enhance existing dolutegravir treatments in clinical settings.
Article Abstract
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC of ~7 nM against wild type HIV-1 and ~10 fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581505 | PMC |
| http://dx.doi.org/10.7554/eLife.46344 | DOI Listing |
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