Protein-protein interactions that occur during fertilization will be investigated. Sperm-egg adhesion and fusion is a multi-step process. Two sperm proteins, fertilin-beta and cyritestin, members of the ADAM family of proteins (A Disintegrin and Metalloprotease), are involved in sperm-egg binding. Biochemical and genetic experiments suggest there are multiple ADAM receptors on the egg. .Chemical probes containing the fertilin-beta or cyritestin binding motifs presented in either monovalent or multivalent format have been developed. These multivalent fertilin-beta mimics are the most potent fertilin-beta-derived inhibitors of fertilization to date. Moreover, these polymers cause parthenogenic egg activation resulting in resumption of meiosis.
The aim of this proposal is to investigate the mechanism of action of these polymers, as well as cyritestin-derived polymers. The investigation will determine whether inhibition is due to direct competition with sperm binding or if it is due to activation of the egg block to polyspermy that results in blocking of sperm fusion. The structural requirements for inhibition versus activation will be identified as well as the egg receptors responsible. The determination of the mechanism(s) of action of the polymers will provide new leads for investigating egg-sperm adhesion, fusion, and activation of development. Understanding the mechanism of action of these compounds will provide insight into possible methods of controlling or aiding fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD038519-05A3
Application #
7095574
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Rankin, Tracy L
Project Start
2000-03-01
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$288,571
Indirect Cost
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Parker, Kathlyn A; Sampson, Nicole S (2016) Precision Synthesis of Alternating Copolymers via Ring-Opening Polymerization of 1-Substituted Cyclobutenes. Acc Chem Res 49:408-17
Lee, Siyeon; Wang, Wei; Lee, Younjoo et al. (2015) Cyclic acetals as cleavable linkers for affinity capture. Org Biomol Chem 13:8445-52
Wu, Linghui; Sampson, Nicole S (2014) Fucose, mannose, and ?-N-acetylglucosamine glycopolymers initiate the mouse sperm acrosome reaction through convergent signaling pathways. ACS Chem Biol 9:468-75
Romulus, Joy; Tan, Li; Weck, Marcus et al. (2013) Alternating ROMP copolymers containing charge-transfer units. ACS Macro Lett 2:749-752
Song, Airong; Walker, Stephen G; Parker, Kathlyn A et al. (2011) Antibacterial studies of cationic polymers with alternating, random, and uniform backbones. ACS Chem Biol 6:590-9
Song, Airong; Parker, Kathlyn A; Sampson, Nicole S (2010) Cyclic alternating ring-opening metathesis polymerization (CAROMP). Rapid access to functionalized cyclic polymers. Org Lett 12:3729-31
Song, Airong; Lee, Jae Chul; Parker, Kathlyn A et al. (2010) Scope of the ring-opening metathesis polymerization (ROMP) reaction of 1-substituted cyclobutenes. J Am Chem Soc 132:10513-20
Baessler, Keith A; Lee, Younjoo; Sampson, Nicole S (2009) Beta1 integrin is an adhesion protein for sperm binding to eggs. ACS Chem Biol 4:357-66
Lee, Younjoo; Sampson, Nicole S (2009) Polymeric ADAM protein mimics interrogate mammalian sperm-egg binding. Chembiochem 10:929-37
Song, Airong; Parker, Kathlyn A; Sampson, Nicole S (2009) Synthesis of copolymers by alternating ROMP (AROMP). J Am Chem Soc 131:3444-5

Showing the most recent 10 out of 19 publications