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dc.contributor.authorMarch, DR
dc.contributor.authorAbbenante, G
dc.contributor.authorBergman, DA
dc.contributor.authorBrinkworth, RI
dc.contributor.authorWickramasinghe, W
dc.contributor.authorBegun, J
dc.contributor.authorMartin, JL
dc.contributor.authorFairlie, DP
dc.date.accessioned2017-10-05T03:05:26Z
dc.date.available2017-10-05T03:05:26Z
dc.date.issued1996
dc.identifier.issn0002-7863
dc.identifier.doi10.1021/ja953790z
dc.identifier.urihttp://hdl.handle.net/10072/347912
dc.description.abstractResults are presented for inhibitors of HIV-1 protease that demonstrate a new strategy for developing peptidomimetics, involving the replacement of flexible segments of peptide substrates with conformationally constrained hydrolytically-stable macrocyclic structural mimics. A 15-membered macrocycle that imitates the tripeptide Phe-Ile-Val was designed and incorporated into the C-terminus of Ac-Leu-Val-Phe-CHOHCH2-{Phe-Ile-Val}-NH2, an inhibitor of HIV-1 protease derived from a substrate sequence. Advantages of the macrocycle over the acyclic peptide include constraining its components into their bioactive conformation and protecting the amide bonds from enzymatic degradation, the cycle being stable to acid, gastric proteases, and plasma. Molecular modeling and X-ray structural studies reveal that the cyclic inhibitors have a unique enzyme-binding mode, the sterically unencumbered hydroxyethylamine isostere binds via both its hydroxyl and protonated nitrogen to the anionic Asp25 catalytic residues. The novel macrocycle superimposes well on the linear peptidic inhibitor for which it was designed as a structural mimic. Structural mimicry led to functional mimicry as shown by comparable inhibition of the protease by cyclic and acyclic molecules. Further modification of the acyclic N-terminus (Leu-Val-Phe) gave stable, water-soluble, potent inhibitors of HIV-1 protease. This approach may have general application to the development of mimetics of other bioactive peptides, including inhibitors of other enzymes.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom3375
dc.relation.ispartofpageto3379
dc.relation.ispartofissue14
dc.relation.ispartofjournalJournal of the American Chemical Society
dc.relation.ispartofvolume118
dc.subject.fieldofresearchChemical sciences
dc.subject.fieldofresearchMedicinal and biomolecular chemistry not elsewhere classified
dc.subject.fieldofresearchcode34
dc.subject.fieldofresearchcode340499
dc.titleSubstrate-based cyclic peptidomimetics of Phe-Ile-Val that inhibit HIV-1 protease using a novel enzyme-binding mode
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorMartin, Jennifer


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