The development of a reversible and non-hormonal male contraceptive will supplement existing birth control options to achieve a significant impact upon the numbers of unwanted pregnancies, a major global problem. This studentship will employ bioportide technologies, bioactive cell penetrating peptides (CPPs), to inhibit the acquisition of human sperm motility at a late stage of epididymal transit.
As recently published and patented, our current lead compound, MSS1, (H-YRSVITFVAVRQIKIWFQNRRMKWKK-NH2), a linear STOPSPERM bioportide (SSB), acts as a dominant-negative modulator of sperm-specific protein-protein interactions (PPIs) to inhibit human sperm motility rapidly and potently. This project will optimise the sequence of MSS1 to define metabolically stable analogues with more drug-like properties suitable for clinical development. Chemical refinement of MSS1 will include the substitution of the penetratin CPP (RQIKIWFQNRRMKWKK ) with metabolically stable cyclic CPPs as delivery vectors. As the AKAP4-derived sequence, YRSVITFVAV, probably binds the intracellular target protein PP1 in a helical conformation, the helicity of second-generation SSBs will be promoted with α-aminoisobutyric acid and other dialkylated helicogenic amino acids.
Microwave-enhanced solid-phase peptide synthesis is a core facility for these developments in RIHS. This activity will graft our optimized PP1-binding sequence (SVITF) and flanking sequences onto cyclic CPP templates, including the orally bioavailable CCP9 and CPP12, and unique cyclic peptides which bind the plasma membrane or intracellular structures of human sperm.
The influence of second-generation SSBs upon human sperm cell parameters (motility and viability) will be determined using sperm class analyses (CASA) and viability assays. The uptake efficacy and intracellular distribution of TAMRA-conjugated fluorescent SSBs will utilize quantitative assays and confocal microscopy. Further selection of SSBs for in vivo studies will employ eukaryotic cell viability assays (necrosis and apoptosis) and studies of mast cell degranulation to deselect materials with undesirable biological characteristics.
Collaborative support from a team lead by Dr Erick Silva (ES), Institute of Biosciences, São Paulo State University (UNESP), Botucatu-SP, Brazil, will support studies to investigate the impact of proven compounds, delivered by intraperitoneal or intravenous routes, upon sperm parameters and reproductive performance. These collaborative studies will also determine the reversibility of SSB treatment, a desirable property of our intended male contraceptive.
This multidisciplinary project provides a unique opportunity to play a major role within our Male Contraceptive Research Consortium (MCRC; https://www.wlv.ac.uk/research/male-contractive-research-consortium-/) and is particularly suitable for graduates with an interest in peptide chemistry and/or intracellular signalling pathways. Full support will be available within RIHS and through an established collaboration with the University of Aveiro, Portugal.
Enquiries email name and address:
Professor John Howl, RIHS, University of Wolverhampton, WV1 1LY
[Email Address Removed]
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