Journal article
The Spermostatic and Microbicidal Actions of Quinones and Maleimides: Toward a Dual-Purpose Contraceptive Agent
Molecular pharmacology, v 76(1)
01 Jul 2009
PMID: 19336525
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
There is an urgent need to develop safe, effective, dual-purpose contraceptive agents that combine the prevention of pregnancy with protection against sexually transmitted diseases. 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, non-oxynol 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 protein kinase A-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 muridarum 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 Major Outer Membrane Protein (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.
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Details
- Title
- The Spermostatic and Microbicidal Actions of Quinones and Maleimides: Toward a Dual-Purpose Contraceptive Agent
- Creators
- Louise M. Hughes - IT UniversityRenate GriffithAlison Carey - Queensland University of TechnologyTrent ButlerScott W. DonneKen W. Beagley - Queensland University of TechnologyR. John Aitken - Univ Newcastle, Sch Environm & Life Sci, Discipline Biol Sci, Fac Sci & IT, Callaghan, NSW 2308, Australia
- Publication Details
- Molecular pharmacology, v 76(1)
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 12
- Grant note
- Australian Research Council Centre of Excellence in Biotechnology and Development; Australian Research Council 252441 / Australian National Health and Medical Research Council; National Health and Medical Research Council (NHMRC) of Australia
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics; College of Medicine; Drexel University
- Web of Science ID
- WOS:000267902900012
- Scopus ID
- 2-s2.0-67649863481
- Other Identifier
- 991020099785504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy