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Optimized peptide based inhibitors targeting the dihydrofolate reductase pathway in cancer

Singh, Amrinder and Deshpande, Neha and Pramanik, Nilkamal and Jhunjhunwala, Siddharth and Rangarajan, Annapoorni and Atreya, Hanudatta S (2018) Optimized peptide based inhibitors targeting the dihydrofolate reductase pathway in cancer. In: SCIENTIFIC REPORTS, 8 .

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Official URL: http://dx.doi.org/10.1038/s41598-018-21435-5


We report the first peptide based hDHFR inhibitors designed on the basis of structural analysis of dihydrofolate reductase (DHFR). A set of peptides were rationally designed and synthesized using solid phase peptide synthesis and characterized using nuclear magnetic resonance and enzyme immunoassays. The best candidate among them, a tetrapeptide, was chosen based on molecular mechanics calculations and evaluated in human lung adenocarcinoma cell line A549. It showed a significant reduction of cell proliferation and an IC50 of 82 mu M was obtained. The interaction of the peptide with DHFR was supported by isothermal calorimetric experiments revealing a dissociation constant K-d of 0.7 mu M and Delta G of -34 +/- 1 kJ mol(-1). Conjugation with carboxylated polystyrene nanoparticles improved further its growth inhibitory effects. Taken together, this opens up new avenues to design, develop and deliver biocompatible peptide based anti-cancer agents.

Item Type: Journal Article
Additional Information: Copy right for the article belong to NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre: Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Depositing User: Id for Latest eprints
Date Deposited: 14 Mar 2018 17:39
Last Modified: 22 Oct 2018 11:32
URI: http://eprints.iisc.ac.in/id/eprint/59168

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