HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

The spermostatic and microbicidal actions of quinones and maleimides: toward a dual-purpose contraceptive agent.

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.
AuthorsLouise M Hughes, Renate Griffith, Alison Carey, Trent Butler, Scott W Donne, Ken W Beagley, R John Aitken
JournalMolecular pharmacology (Mol Pharmacol) Vol. 76 Issue 1 Pg. 113-24 (Jul 2009) ISSN: 1521-0111 [Electronic] United States
PMID19336525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • A Kinase Anchor Proteins
  • AKAP3 protein, human
  • AKAP4 protein, human
  • Anti-Bacterial Agents
  • Contraceptive Agents
  • Maleimides
  • Quinones
  • Cyclic AMP-Dependent Protein Kinases
Topics
  • A Kinase Anchor Proteins (physiology)
  • Alkylation
  • Anti-Bacterial Agents (pharmacology)
  • Cell Survival (drug effects)
  • Chlamydia muridarum (drug effects)
  • Contraceptive Agents (pharmacology)
  • Cyclic AMP-Dependent Protein Kinases (physiology)
  • Humans
  • Male
  • Maleimides (pharmacology)
  • Quinones (pharmacology)
  • Sexually Transmitted Diseases (prevention & control)
  • Signal Transduction
  • Sperm Motility (drug effects)
  • Spermatozoa (drug effects)
  • Structure-Activity Relationship

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: