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

Hughes, Louise, Griffith, Renate, Carey, Alison, Butler, Trent, Donne, Scott, Beagley, Kenneth, & Aitken, R (2009) The spermostatic and microbicidal actions of quinones and malemides : towards a dual-purpose contraceptive agent. Molecular Pharmacology, 76(1), pp. 113-124.

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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, 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 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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14 citations in Web of Science®

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ID Code: 42747
Item Type: Journal Article
Keywords: Spermocide, Chlamydia, Contraception
DOI: 10.1124/mol.108.053645
ISSN: 0026-895X
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > CLINICAL SCIENCES (110300) > Infectious Diseases (110309)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > CLINICAL SCIENCES (110300) > Venereology (110324)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PAEDIATRICS AND REPRODUCTIVE MEDICINE (111400) > Reproduction (111404)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PHARMACOLOGY AND PHARMACEUTICAL SCIENCES (111500)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 13 Jul 2011 13:06
Last Modified: 05 Feb 2015 03:28

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