HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues.
Drug resistance
HIV-1 protease
Protease inhibitors
SAR studies
X-ray structure
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
05 Sep 2023
05 Sep 2023
Historique:
received:
27
02
2023
revised:
15
05
2023
accepted:
16
05
2023
pmc-release:
05
09
2024
medline:
19
6
2023
pubmed:
28
5
2023
entrez:
27
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37244161
pii: S0223-5234(23)00467-1
doi: 10.1016/j.ejmech.2023.115501
pmc: PMC10332405
mid: NIHMS1905493
pii:
doi:
Substances chimiques
HIV Protease Inhibitors
0
Darunavir
YO603Y8113
Peptide Hydrolases
EC 3.4.-
HIV Protease
EC 3.4.23.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115501Subventions
Organisme : NIGMS NIH HHS
ID : P01 GM109767
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM135919
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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