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Interfacial inhibitors.

ABSTRACT: Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein-DNA complexes by binding at protein-DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitors and HIV integrase inhibitors. Additional examples of recent interfacial inhibitors for protein-DNA interfaces are provided, as well as prospects for targeting previously 'undruggable' targets including transcription, replication and chromatin remodeling complexes. References and discussion are included for interfacial inhibitors of protein-protein interfaces.

SUBMITTER: Pommier Y

PROVIDER: S-EPMC7747010 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Interfacial inhibitors.

Pommier Yves Y Kiselev Evgeny E Marchand Christophe C

Bioorganic & medicinal chemistry letters 20150718 18

Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein-DNA complexes by binding at protein-DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitor ...[more]

PMID: 26235949

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Project description:Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly interfacial inhibitors that show antiviral activity.

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Interfacial inhibitors.

Publications

Interfacial inhibitors.

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