Poster O11 - Targeting sperm-specific proteins with novel cyclic peptides for male contraception

Introduction: Almost half of all pregnancies are unintended, with >60% of these events resulting in termination. A range of contraceptive options for females dominate the market, with options for males being limited to condoms (with a failure rate of 15-20%) or vasectomy. With no approved male-focused drug contraceptives on the market, there is an unmet need for male-focused contraceptives. Male-focused contraceptives under development are (i) hormonal or (ii) non-hormonal in nature; hormonal-based contraceptives aim to modulate the hypothalamic/GnRH)-pituitary(LH/FSH)-testicular(T) axis but are linked to increased susceptibility to carcinogenesis, cardiovascular defects and other dysfunctions. Non-hormonal male contraceptive strategies have shortfalls including (ii) targeting ubiquitous biochemical mechanisms (e.g., synthesis of retinoic acid (RA) or binding to its RAR receptor), (ii) short half-lives or off-target effects (e.g., bromodomain testis-specific proteins inhibitors) or (iii) involve vaccinations that are invasive and not readily reversible. These results highlight the significant gap for novel male contraceptive alternatives that ideally, (i) are inherently easy to self-administer, (ii) have significant half-life in vivo, (iii) be highly tolerated with minimal side effects and (iv) be non-immunogenic, (v) have excellent stability at a range of temperatures, (vi) be reversible and (vii) be low cost of goods to manufacture.

Materials and

Methods: A number of sperm-specific proteins bind oolemma-derived receptors to mediate fertilization. We hypothesized that selectively targeting sperm-derived targets in the male with inhibitory peptides would block fertilization and thus represent an efficacious male contraception. ’Cyclic’ peptides are linear peptides bonded into singular or multiple circular structures. They provide numerous, therapeutically-relevant advantages over their linear counterparts, including (i) a longer half life in vivo through maintaining an ordered secondary structure and avoiding endopeptidase hydrolysis, (ii) have enhanced cellular and extracellular membrane permeability, (iii) present a potentially larger target interacting interface via their circular structure, (iv) can be administered orally or nasal spray (or injection), (v) generally have very low immunogenicity, and (vi) can be manufactured at low cost. Therefore, our aim was to rationally design inhibitory cyclic peptides that block sperm-derived targets, and subsequent fertilization.

Results, Conclusions, and Discussions: We resolved predicted structures of (mouse) sperm-derived targets from primary sequence using AI/ML (RoseTTaFold) for use in in silico molecular simulations (RosettaScripts) to derive promising contraceptive cyclic peptides that bind the oolemmal receptor binding domains of sperm proteins. Promising cyclic peptide candidate/s have been derived and synthesized, and current studies are underway to test the safety/biocompatability of putative peptides in vivo, and ability to inhibit fertilization in vitro (IVF) and in vivo.
In conclusion, with considerable unwanted pregnancy rates and many leading to termination, combined with limited options for males contraceptives on the market, there is an unmet need for the development of novel, safe and efficacious male contraceptive options. Cyclic peptide-based therapeutics possess numerous conceivable advantages over other peptide therapeutics that could be exploited for contraceptive options, including their enhanced ability to cross cellular and tissue membranes.
Development of a safe and easily manufacturable male contraceptive will have a significant impact on society and healthcare. The focus of R&D should be the development of therapeutics that circumvent the off-target effects inherent in current hormonal and non-hormonal strategies under development. With this objective in mind, we propose cyclic peptides are an attractive platform to explore for the development of novel male contraceptives.

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