Blockade of GRTH/DDX25 Phosphorylation by Cyclic Peptides Provides an Avenue for Developing a Nonhormonal Male Contraceptive

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Oct 4

PMID 34601876

Citations 1

Authors

Murugananthkumar Raju

Raghuveer Kavarthapu

Rajakumar Anbazhagan

Sergio A Hassan

Maria L Dufau

Affiliations

Soon will be listed here.

Abstract

Gonadotropin-regulated testicular RNA helicase (GRTH)/DDX25 is a DEAD-box RNA helicase essential for the completion of spermatogenesis. Our previous studies indicated that blocking the GRTH phospho-site or perturbing the GRTH/protein kinase A (PKA) interface could provide an avenue for developing a nonhormonal male contraceptive. In this study, cyclic peptides were rationally designed and synthesized as promising therapeutic agents. The peptides showed effective delivery into COS-1 and germ cells and a dose-dependent inhibitory effect on GRTH phosphorylation. The peptides inhibit GRTH phosphorylation in the presence of PKA, and binding to the helicase resulted in thermal stabilization of non-phospho GRTH. Increased efficiency in fluorescence resonance energy transfer (FRET) assay revealed their interaction with GRTH. Cyclic peptide exposure of cultures from mice seminiferous tubules resulted in significant inhibition of phospho GRTH. These peptides did not exhibit toxicity. Effective delivery and targeted decrease of in vitro expression of phospho GRTH by cyclic peptides provide a promising angle to develop effective compounds as a nonhormonal male contraceptive.

Citing Articles

Discovering a Reversible Male Contraceptive Agent Derived from Lonidamine.

Gong S, Zhu S, Zhou P, Cheng C, Li W, Yao W ACS Omega. 2023; 8(20):18245-18254.

PMID: 37251173 PMC: 10210193. DOI: 10.1021/acsomega.3c01840.

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