Multivalent fertilinbeta oligopeptides: the dependence of fertilization inhibition on length and density.
The sperm protein fertilinbeta, a member of the ADAM family of proteins, is implicated in sperm-egg binding in all mammals studied to date. Multivalent inhibitors containing the three amino acid binding sequence of fertilinbeta, ECD, have been shown previously to be more effective inhibitors of fertilization than their monovalent counterparts. Here, we probed sperm-egg interactions with ruthenium-catalyzed ring-opening metathesis polymers that contained from 3 to 70 ECD pharmacophores in densities ranging from 10% to 100%. Evaluation of the polymer potencies, and synthesis of a triblock copolymer from two building blocks, revealed that two multivalent contacts are sufficient for maximal inhibition, and that the distance between ECD pharmacophores required is 7-9 monomers spanning 4-5 nm. We conclude that inhibition requires recruitment of two receptors on the egg surface into an inhibitory complex.
Baessler
Keith A
KA
Biochemistry and Structural Biology Graduate Program, Stony Brook University, Stony Brook, New York 11794, USA.
Lee
Younjoo
Y
Roberts
Kenny S
KS
Facompre
Nicole
N
Sampson
Nicole S
NS
D051722:ADAM Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002384:Catalysis; D005260:Female; D000072196:Fertilins; D005306:Fertilization / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry; D013084:Sperm-Ovum Interactions / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D008562:Membrane Glycoproteins; D009842:Oligopeptides; D012428:Ruthenium; D051722:ADAM Proteins; D000072196:Fertilins