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

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

doi:10.1016/j.ejmech.2023.115501

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

Journal Article · Thu May 18 00:00:00 EDT 2023 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2023.115501· OSTI ID:2423456

Lockbaum, Gordon J. ^[1]; Rusere, Linah N. ^[1]; Henes, Mina ^[1]; Kosovrasti, Klajdi ^[1]; Rao, Desaboini Nageswara ^[1]; Spielvogel, Ean ^[2]; Lee, Sook-Kyung ^[2]; Nalivaika, Ellen A. ^[1]; Swanstrom, Ronald ^[2]; Yilmaz, Nese Kurt ^[1]; Schiffer, Celia A. ^[1]; ^[1]

Univ. of Massachusetts, Worcester, MA (United States). Chan Medical School
University of North Carolina, Chapel Hill, NC (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423456

Alternate ID(s):: OSTI ID: 1975308

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Vol. 257; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

60 APPLIED LIFE SCIENCES
Drug resistance
HIV-1 protease
Protease inhibitors
SAR studies
X-ray structure

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

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