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dc.contributor.authorRusere, Linah
dc.contributor.authorLockbaum, Gordon J.
dc.contributor.authorHenes, Mina
dc.contributor.authorLee, Sook-Kyung
dc.contributor.authorSpielvogel, Ean
dc.contributor.authorRao, Desaboini Nageswara
dc.contributor.authorKosovrasti, Klajdi
dc.contributor.authorNalivaika, Ellen A.
dc.contributor.authorSwanstrom, Ronald
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorAli, Akbar
dc.date2022-08-11T08:08:24.000
dc.date.accessioned2022-08-23T15:54:11Z
dc.date.available2022-08-23T15:54:11Z
dc.date.issued2020-07-16
dc.date.submitted2020-07-22
dc.identifier.citation<p>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. <a href="https://doi.org/10.1021/acs.jmedchem.0c00529">Link to article on publisher's site</a></p>
dc.identifier.issn0022-2623 (Linking)
dc.identifier.doi10.1021/acs.jmedchem.0c00529
dc.identifier.pmid32672965
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29501
dc.description.abstractThe 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32672965&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1021/acs.jmedchem.0c00529
dc.rightsThis 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.
dc.subjectHIV-1
dc.subjectprotease Inhibitors
dc.subjectstructural analysis
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal and Pharmaceutical Chemistry
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectStructural Biology
dc.subjectViruses
dc.titleStructural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere
dc.typeAccepted Manuscript
dc.source.journaltitleJournal of medicinal chemistry
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2735&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1723
dc.identifier.contextkey18616857
refterms.dateFOA2022-08-23T15:54:12Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/1723
dc.contributor.departmentSchiffer Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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