University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Schiffer Lab

Publication Date

2020-07-16

Document Type

Article Postprint

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal Chemistry and Pharmaceutics | Structural Biology | Viruses

Abstract

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights for optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.

Keywords

HIV-1, protease Inhibitors, structural analysis

Rights and Permissions

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © 2020 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.0c00529. Accepted manuscript posted after 12-month embargo as allowed by publisher's Journal Publishing Agreement User’s Guide at https://pubs.acs.org/userimages/ContentEditor/1285231362937/jpa_user_guide.pdf.

DOI of Published Version

10.1021/acs.jmedchem.0c00529

Source

Rusere LN, Lockbaum GJ, Henes M, Lee SK, Spielvogel E, Rao DN, Kosovrasti K, Nalivaika EA, Swanstrom R, Kurt Yilmaz N, Schiffer CA, Ali A. Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere. J Med Chem. 2020 Jul 16. doi: 10.1021/acs.jmedchem.0c00529. Epub ahead of print. PMID: 32672965. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Journal of medicinal chemistry

PubMed ID

32672965

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