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

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.

Discovering a Reversible Male Contraceptive Agent Derived from Lonidamine

“…Also, there is an increasing need to have men share the burden of family planning in both developed and developing countries . As such, there is an urgent need for safe and reversible non-hormonal male contraceptives. , Based on studies of the past two decades, an ideal agent for the control of male fertility is one that has a selective inhibitory action on the germinal epithelium of the testes by blocking spermatogenesis, , long before mature spermatozoa are formed. Adjudin was an anti-spermatogenic compound that exerted its effects on the seminiferous tubules, which disrupted the adhesion of spermatids to Sertoli cells in the testis .…”