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Investigating the inhibitory potential of 2-Aminopurine metal complexes against serine/threonine protein kinases from Mycobacterium tuberculosis.

Vaibhav Singh, Bais and Balaram, Mohapatra and Nadim, Ahamad and Sanjana, Boggaram and Sandeep, Verma and Balaji, Prakash (2018) Investigating the inhibitory potential of 2-Aminopurine metal complexes against serine/threonine protein kinases from Mycobacterium tuberculosis. Tuberculosis, 108. pp. 47-55.

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Abstract

Tuberculosis – a disease caused by Mycobacterium tuberculosis (Mtb), is one of the most devastating. The discovery of Ser/Thr protein kinases (STPKs) in Mtb opened a new avenue for developing anti-tubercular inhibitors. The in-vivo inhibitory effects of many metal ions have been demonstrated in literature. But, one of the limitations of metal ions as inhibitors is their inability to traverse the hydrophobic membrane due to polar nature and their propensity for nonspecific interactions. To overcome this, we attached a metal ion to 2-A9P – an analog derived from a cell permeable scaffold, 2-Aminopurine (2-AP) which is a known kinase inhibitor. We investigated the inhibitory potential of 2-AP and its analog 2-A9P against protein kinase B (PknB) and showed that both of these can inhibit Mtb STPKs. Next, we evaluated the latent inhibitory activity of metal ions and for the first time showed that they can inhibit the phosphotransfer reaction in PknB, PknG and PknL. Subsequently, 6 different metal complexes (MC) of 2-A9P were used for inhibitory studies and their estimated IC50 values show that most MCs inhibited PknB with low micromolar potency. Further, MIC values determined for the six MCs against Mtb showed that MC-4 and MC-6 exhibit whole cell inhibitory activity. Cytotoxicity studies show that MC-4 and MC-6 do not affect cell viability of A549 cell lines, suggesting that these inhibitors can be further developed as anti-tubercular agents.

Item Type: Article
Uncontrolled Keywords: Tuberculosis, Protein kinases, Metal complexes, Inhibitors
Subjects: 600 Technology > 01 Medical sciences
600 Technology > 08 Food technology > 16 Nutritive value > 05 Enzymes
Divisions: Molecular Nutrition
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 14 Feb 2018 05:20
Last Modified: 14 Feb 2018 05:20
URI: http://ir.cftri.com/id/eprint/13407

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