Wednesday, April 24, 2024
4/24/2024
Summary Development of male contraceptives has lagged far behind that of female contraceptives. Current physical options for male birth control have limitations with respect to reliability, consistency of use, and invasiveness, respectively. Inhibiting sperm production by decreasing testosterone levels would also cause unacceptable side effects. Thus, our long-term objective is to develop a contraceptive that blocks the late stage of spermatogenesis without the use of hormones so that the effect is reversible with fewer/no side effects. The manchette is a transient microtubule-containing structure that is present only in elongating spermatids, and genetic disruption of the manchette structure/function results in male infertility. Importantly, we have discovered that the function of the machete in spermatogenesis requires the interaction between meiosis expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG). A single point mutation in MEIG1 or PACRG that disrupts the interaction of the two proteins also disrupts spermatogenesis resulting in pure male infertility. Interaction between MEIG1 and PACRG is conserved in humans. We hypothesize that compounds that disrupt the MEIG1/PACRG interaction can be developed into safer and effective male contraceptives. Availability of the MEIG1/PACRG structure makes it possible to in silico virtual and artificial intelligence (AI) screens for small molecules that block MEIG1/PACRG interaction, with biochemical validation hits. Thus, the objective of the present application is to conduct in silico virtual and AI screens to identify small molecules that block the interaction of MEIG1 and PACRG which can be developed into leads for male contraceptives. To this end, we provide preliminary data for a robust G. princeps luciferase complementation assay for the interaction of MEIG1 and PACRG that can be readily used to validate the effect of the small molecules identified from the virtual and AI screens. In addition, a fragment library for compounds is available for a physical screen and the fragments that interrupt MEIG1/PACRG interaction can also be used for drug development in the future. Thus, we propose the following two aims: 1: To complete the in silico virtual screen and to examine the effect of small molecules identified by the in silico virtual and AI screens on interrupting MEIG1/PACRG interaction; 2: To screen a fragment library for compounds that disrupt the MEIG1/PACRG interaction. We expect to identify small molecules/fragments that have the potential to interrupt MEIG1/PACRG interaction and test the effect of selective small molecules/fragments using the established assay. Given that global Meig1 knockout mice and both single amino acid mutant MEIG1 and PACRG mice showed a male infertility only phenotype, targeting MEIG1/PACRG interaction is believed to cause few/no side effects. The ultimate goal of the proposed studies is to advance a male contraceptive to inhibit sperm formation/function to the stage of filing an investigational new drug (IND) application. The discovery and development of a male “pill” will benefit the general population and reduce unintended pregnancies.
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