2. Academic Validation
  3. HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues

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.
Gordon J Lockbaum 1,  Linah N Rusere 1,  Mina Henes 1,  Klajdi Kosovrasti 1,  Desaboini Nageswara Rao 1,  Ean Spielvogel 2,  Sook-Kyung Lee 2,  Ellen A Nalivaika 1,  Ronald Swanstrom 2,  Nese Kurt Yilmaz 1,  Celia A Schiffer 3,  Akbar Ali 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, United States.
  • 2 Department of Biochemistry and Biophysics, And the UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
  • 3 Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, United States. Electronic address: [email protected].
  • 4 Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, United States. Electronic address: [email protected].
PMID: 37244161 DOI: 10.1016/j.ejmech.2023.115501
Abstract

Protease 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.

Keywords

Drug resistance; HIV-1 protease; Protease inhibitors; SAR studies; X-ray structure.

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