The sperm-penetrating bioactive peptide MSS1, YRSVITFVAVRQIKIWFQNRRMKWKK, a prototypic STOPSPERM bioportide (SSB), acts as a dominant-negative modulator of human sperm-specific protein-protein interactions (PPIs) to rapidly inhibit motility.
Aligned with the Male Contraceptive Initiative priority of targeting sperm motility, this research award will enable the synthesis and evaluation of metabolically stable and orally bioavailable SSBs as reversible inhibitors of normal fertilization.
Biological profiling will select optimized SSBs with pharmacodynamic properties compatible with animal model studies. Proof-of-concept in vivo investigations will identify SSB candidates for continued development as reversible male contraceptives, specifically acting upon the acquisition of sperm motility during epididymal transport.
Research aims
The overriding objective of this study is to define the efficacy of second generation cyc-SSBs that are metabolically stable and orally bioavailable formulations of first-generation compounds. The cyclotide platform chosen for this purpose is a head-to-tail macrocycle stabilised by three disulfide bonds arranged in a cystine knot. The exposed loop structures of cyclotides ablate PPIs both in vitro and in vivo. Lead compounds will be subjected to detailed biological evaluation and synthesised in sufficient quantities for pre-clinical testing in rodents.
The project is funded by the Male Contraceptive Initiative.
Project team
Collaborators
University of Aveiro, University of Queensland, Universidade Estadual Paulista Júlio de Mesquita Filho