Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Interfacial inhibitors. 2623 49

Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein-DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA. These molecules were able to inhibit several enzymes possessing non-sequence-selective DNA-binding properties, including topoisomerase 1 and HIV-1 integrase, presumably through specific foldamer-protein interactions, whereas sequence-selective enzymes were not inhibited. Such modular and synthetically accessible DNA mimics provide a versatile platform to design novel inhibitors of protein-DNA interactions.
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PMID:Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA. 2961 Apr 64


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