HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues
AuthorsLockbaum, Gordon J
Rusere, Linah N
Rao, Desaboini Nageswara
Nalivaika, Ellen A
Yilmaz, Nese Kurt
Schiffer, Celia A
Document TypeJournal Article
MetadataShow full item record
AbstractProtease inhibitors are the most potent antivirals against HIV-1, but they still lose efficacy against resistant variants. Improving the resistance profile is key to developing more robust inhibitors, which may be promising candidates for simplified next-generation antiretroviral therapies. In this study, we explored analogs of darunavir with a P1 phosphonate modification in combination with increasing size of the P1' hydrophobic group and various P2' moieties to improve potency against resistant variants. The phosphonate moiety substantially improved potency against highly mutated and resistant HIV-1 protease variants, but only when combined with more hydrophobic moieties at the P1' and P2' positions. Phosphonate analogs with a larger hydrophobic P1' moiety maintained excellent antiviral potency against a panel of highly resistant HIV-1 variants, with significantly improved resistance profiles. The cocrystal structures indicate that the phosphonate moiety makes extensive hydrophobic interactions with the protease, especially with the flap residues. Many residues involved in these protease-inhibitor interactions are conserved, enabling the inhibitors to maintain potency against highly resistant variants. These results highlight the need to balance inhibitor physicochemical properties by simultaneous modification of chemical groups to further improve resistance profiles.
SourceLockbaum GJ, Rusere LN, Henes M, Kosovrasti K, Rao DN, Spielvogel E, Lee SK, Nalivaika EA, Swanstrom R, Yilmaz NK, Schiffer CA, Ali A. HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues. Eur J Med Chem. 2023 Sep 5;257:115501. doi: 10.1016/j.ejmech.2023.115501. Epub 2023 May 18. PMID: 37244161; PMCID: PMC10332405.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52364
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