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The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction.

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Dalton N, Gordon CP, Boyle TP, Vandegraaf N, Deadman J, Rhodes DI, Coates JA, Pyne SG, Keller PA, Bremner JB,


Dalton N, Gordon CP, Boyle TP, Vandegraaf N, Deadman J, Rhodes DI, Coates JA, Pyne SG, Keller PA, Bremner JB, (click to view)

Dalton N, Gordon CP, Boyle TP, Vandegraaf N, Deadman J, Rhodes DI, Coates JA, Pyne SG, Keller PA, Bremner JB,

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Organic & biomolecular chemistry 2016 05 2614(25) 6010-23 doi 10.1039/c6ob00950f

Abstract

From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.

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