HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands to Optimize Hydrogen Bonding in the Substrate Envelope
Authors
Rusere, Linah N.Lockbaum, Gordon J.
Lee, Sook-Kyung
Henes, Mina
Kosovrasti, Klajdi
Spielvogel, Ean
Nalivaika, Ellen A.
Swanstrom, Ronald
Yilmaz, Nese Kurt
Schiffer, Celia A.
Ali, Akbar
Document Type
Journal ArticlePublication Date
2019-08-21Keywords
BiochemistryMedicinal Chemistry and Pharmaceutics
Medicinal-Pharmaceutical Chemistry
Molecular Biology
Structural Biology
Metadata
Show full item recordAbstract
A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while staying within the substrate envelope. Stereoisomers of 4-(1-hydroxyethyl)benzene and 4-(1,2-dihydroxyethyl)benzene moieties were explored as P2' ligands providing pairs of diastereoisomers epimeric at P2', which exhibited distinct potency profiles depending on the configuration of the hydroxyl group and size of the P1' group. While compounds with the 4-(1-hydroxyethyl)benzene P2' moiety maintained excellent antiviral potency against a panel of multidrug-resistant HIV-1 strains, analogues with the polar 4-(1,2-dihydroxyethyl)benzene moiety were less potent, and only the (R)-epimer incorporating a larger 2-ethylbutyl P1' group showed improved potency. Crystal structures of protease-inhibitor complexes revealed strong hydrogen bonding interactions of both (R)- and (S)-stereoisomers of the hydroxyethyl group with Asp30'. Notably, the (R)-dihydroxyethyl group was involved in a unique pattern of direct hydrogen bonding interactions with the backbone amides of Asp29' and Asp30'. The SAR data and analysis of crystal structures provide insights for optimizing these promising HIV-1 protease inhibitors.Source
J Med Chem. 2019 Aug 6. doi: 10.1021/acs.jmedchem.9b00838. [Epub ahead of print] Link to article on publisher's site
DOI
10.1021/acs.jmedchem.9b00838Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48893PubMed ID
31386368Related Resources
ae974a485f413a2113503eed53cd6c53
10.1021/acs.jmedchem.9b00838