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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Abstract

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
Publication:	SCIENTIFIC REPORTS
Publisher:	NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
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)
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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