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Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Chakrabarty, Subhra Prakash and Ramapanicker, Ramesh and Mishra, Roli and Chandrasekaran, Srinivasan and Balaram, Hemalatha (2009) Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity. In: Bioorganic & Medicinal Chemistry, 17 (23). pp. 8060-8072.

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Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on N epsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI2 and E.NAD(+).I-2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket commodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to Elsevier Science.
Keywords: Sir2 activity; Peptide inhibitors; Carbohydrate conjugates; Click chemistry; Parabolic inhibition
Department/Centre: Division of Chemical Sciences > Organic Chemistry
Depositing User: Id for Latest eprints
Date Deposited: 01 Dec 2009 06:02
Last Modified: 19 Sep 2010 05:53
URI: http://eprints.iisc.ac.in/id/eprint/25034

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