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Optimized peptide based inhibitors targeting the dihydrofolate reductase pathway in cancer.

Optimized peptide based inhibitors targeting the dihydrofolate reductase pathway in cancer.
Author Information (click to view)

Singh A, Deshpande N, Pramanik N, Jhunjhunwala S, Rangarajan A, Atreya HS,


Singh A, Deshpande N, Pramanik N, Jhunjhunwala S, Rangarajan A, Atreya HS, (click to view)

Singh A, Deshpande N, Pramanik N, Jhunjhunwala S, Rangarajan A, Atreya HS,

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Scientific reports 2018 02 168(1) 3190 doi 10.1038/s41598-018-21435-5

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 ICof 82 µM was obtained. The interaction of the peptide with DHFR was supported by isothermal calorimetric experiments revealing a dissociation constant Kof 0.7 µM and ΔG of -34 ± 1 kJ mol. 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.

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