Department of Biochemistry and Molecular Pharmacology; Schiffer Lab
Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal Chemistry and Pharmaceutics | Structural Biology | Viruses
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.
HIV-1, protease Inhibitors, structural analysis
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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
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
Journal of medicinal chemistry
Rusere L, Lockbaum GJ, Henes M, Lee S, Spielvogel E, Rao DN, Kosovrasti K, Nalivaika EA, Swanstrom R, Yilmaz NK, Schiffer CA, Ali A. (2020). Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1021/acs.jmedchem.0c00529. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1723
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