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  • Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease

    Author(s)
    Martin, JL
    Begun, J
    Schindeler, A
    Wickramasinghe, WA
    Alewood, D
    Alewood, PF
    Bergman, DA
    Brinkworth, RI
    Abbenante, G
    March, DR
    Reid, RC
    Fairlie, DP
    Griffith University Author(s)
    Martin, Jennifer
    Year published
    1999
    Metadata
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    Abstract
    High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15−17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained ...
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    High-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15−17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a β-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine−aspartate interaction induces a 1.5 Å N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba67,95]HIVPR and [Lys7,Ile33,Aba67,95]HIVPR used in this work were shown to have very similar crystal structures.
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    Journal Title
    Biochemistry
    Volume
    38
    Issue
    25
    DOI
    https://doi.org/10.1021/bi990174x
    Subject
    Medicinal and biomolecular chemistry
    Biochemistry and cell biology
    Biochemistry and cell biology not elsewhere classified
    Medical biochemistry and metabolomics
    Publication URI
    http://hdl.handle.net/10072/347878
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