The spermostatic and microbicidal actions of quinones and maleimides: towards a dual purpose contraceptive agent

There is an urgent need to develop safe, effective dual-purpose contraceptive agents that combine the prevention of pregnancy with protection against sexually transmitted disease. Here we report the identification of a group of compounds that on contact with human spermatozoa induce a state of ‘spermostasis’, characterized by the extremely rapid inhibition of sperm movement without compromising cell viability. These spermostatic agents were more active and significantly less toxic than the reagent in current clinical use, nonoxynol 9, giving therapeutic indices (ratio of spermostatic to cytotoxic activity) that were orders of magnitude greater than this traditional spermicide. Although certain compounds could trigger reactive oxygen species generation by spermatozoa, this activity was not correlated with spermostasis. Rather, the latter was associated with alkylation of two major sperm tail proteins that were identified as A Kinase Anchoring Proteins (AKAP3 and AKAP4) by mass spectrometry. As a consequence of disrupted AKAP function, the abilities of cAMP to drive PKA-dependent activities in the sperm tail such as the activation of SRC and the consequent stimulation of tyrosine phosphorylation, were suppressed. Furthermore, analysis of microbicidal activity using Chlamydia, revealed powerful inhibitory effects at the same low micromolar doses that suppressed sperm movement. In this case, the microbicidal action was associated with alkylation of MOMP, a major Chlamydial membrane protein. Taken together, these results have identified for the first time a novel set of cellular targets and chemical principles capable of providing simultaneous defense against both fertility and the spread of sexually transmitted disease. This article has not been copyedited and formatted. The final version may differ from this version. Molecular Pharmacology Fast Forward. Published on March 31, 2009 as DOI: 10.1124/mol.108.053645 at A PE T Jornals on O cber 9, 2017 m oharm .aspeurnals.org D ow nladed from