Optimized peptide based inhibitors targeting the dihydrofolate reductase pathway in cancer

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 µM was obtained. The interaction of the peptide with DHFR was supported by isothermal calorimetric experiments revealing a dissociation constant Kd of 0.7 µM and ΔG 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.

Ultrasonic De-cross-linking of the pH- and Magneto-Responsive PHEMA/PMMA Microgel to Janus Nanoparticles: A New Synthesis Based on “Grafting from”/“Grafting to” Polymerization

“…MTX has proven to be an effective targeting agent due to the presence of folate receptors on the cell membranes of different kinds of cancer cells. 31 Therefore, in order to increase the smartness of nanoparticles, MTX was chemically grafted to the PHEMA through esterification reaction ( Scheme S3 ).…”

Structure-based inhibitory peptide design targeting peptide-substrate binding site in EGFR tyrosine kinase

“…Over the recent years, peptide based therapeutics have been considered as a promising and novel approach to treat diseases, particularly cancers. Several favorable characteristics of inhibitory peptides including ease of synthesis and modification, low toxicity, biocompatibility and the higher target selectivity and potency make them effective alternatives to small chemical drugs [17–20].…”

Studies on the Interaction between Poly-Phosphane Gold(I) Complexes and Dihydrofolate Reductase: An Interplay with Nicotinamide Adenine Dinucleotide Cofactor

“…The antifolate treatments may afford eventual resistance, which is one of the most important serious side effects observed, resulting in a complete loss of efficacy [9,10]. Then, the identification of new entities possessing the skill to inhibit DHFR becomes a challenging issue, as well as the study of the mechanism developing the drug resistance [11,12]. Whilst this latter aspect has been approached, the research of innovative antifolate compounds has been neglected.…”

“…Whilst this latter aspect has been approached, the research of innovative antifolate compounds has been neglected. The design of antifolate compounds was mainly led by considering structural DHF analogies [11], and few alternative molecules have been tested as DHFR inhibitors [12]. In recent research, gold(I) azolate/phosphane compounds (where the phosphane was PPh 3 , and the azolate were some 3,5-di-substituted pyrazoles and 4,5-di-substituted imidazoles) were found to be cytotoxic in vitro against many panels of cancer cells, and two of them were found to be strongly active also in vivo on the treatment of BBLC sick syngeneic mice.…”