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    Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere

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    Authors
    Rusere, Linah
    Lockbaum, Gordon J.
    Henes, Mina
    Lee, Sook-Kyung
    Spielvogel, Ean
    Rao, Desaboini Nageswara
    Kosovrasti, Klajdi
    Nalivaika, Ellen A.
    Swanstrom, Ronald
    Yilmaz, Nese Kurt
    Schiffer, Celia A.
    Ali, Akbar
    Show allShow less
    UMass Chan Affiliations
    Schiffer Lab
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Accepted Manuscript
    Publication Date
    2020-07-16
    Keywords
    HIV-1
    protease Inhibitors
    structural analysis
    Amino Acids, Peptides, and Proteins
    Biochemistry
    Enzymes and Coenzymes
    Medicinal and Pharmaceutical Chemistry
    Medicinal Chemistry and Pharmaceutics
    Structural Biology
    Viruses
    
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    Show full item record
    Link to Full Text
    https://doi.org/10.1021/acs.jmedchem.0c00529
    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.
    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

    DOI
    10.1021/acs.jmedchem.0c00529
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29501
    PubMed ID
    32672965
    Related Resources

    Link to Article in PubMed

    Rights
    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.
    ae974a485f413a2113503eed53cd6c53
    10.1021/acs.jmedchem.0c00529
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    UMass Chan Faculty and Researcher Publications
    Schiffer Lab Publications

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