title: Epididymal protein targets: a brief history of the development of epididymal protease inhibitor as a contraceptive.
abstract: The Laboratories for Reproductive Biology at the University of North  Carolina at Chapel Hill began collaboration with Human Genome Sciences  (Rockville, Maryland) to sequence a human epididymal library and identify  epididymal-specific genes. Among the first clones obtained from Human Genome  Sciences was a clone for EPPIN (official symbol, SPINLW1).  Our laboratory has described EPPIN (epididymal protease inhibitor) as  a novel gene on human chromosome 20q12-13.2 that encodes a cysteine-rich  protein containing both Kunitz-type and WAP-type 4-disulfide core consensus  sequences that characterize it as a protease inhibitor. EPPIN  expresses 3 mRNA splice variants that encode 2 protein isoforms found in the  testis and epididymis. Of the 2 isoforms, 1 is secreted and 1 lacks a  secretory signal piece. EPPIN is predominantly a dimer, although multiples  often exist, and in its native form, EPPIN is found on the sperm surface  complexed with lactotransferrin and clusterin. During ejaculation, semenogelin  from the seminal vesicles is bound to the EPPIN protein complex, initiating a  series of events that define EPPIN's function: modulating prostate-specific  antigen (PSA) activity, providing antimicrobial protection, and binding  semenogelin, thereby inhibiting sperm motility. As PSA hydrolyzes semenogelin  in the ejaculate coagulum, spermatozoa gain progressive motility. Using  immunization as a tool to study antigen function, we demonstrated that EPPIN  is essential for fertility because immunization of male monkeys with  recombinant EPPIN results in complete, but reversible, contraception. To  exploit our understanding of EPPIN's function, we have developed a  high-throughput screen to look for compounds that inhibit EPPIN-semenogelin  interaction and mimic anti-EPPIN, inhibiting sperm motility. These compounds  are now being developed into a nonhormonal male contraceptive.
authors: Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, NC 27599-7090, USA. morand@unc.edu
authors: Michael G
authors: MG
authors: O'Rand
authors: Esther E
authors: EE
authors: Widgren
authors: Katherine G
authors: KG
authors: Hamil
authors: Erick J
authors: EJ
authors: Silva
authors: Richard T
authors: RT
authors: Richardson
mesh_terms: D000818:Animals; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D004542:Ejaculation; D004822:Epididymis / Q000187:drug effects* / Q000201:enzymology*; D005306:Fertilization; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029607:Seminal Vesicle Secretory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013081:Sperm Motility; D013737:Testis / Q000378:metabolism
chemical_list: D003272:Contraceptive Agents, Male; C431553:Eppin protein, human; D011480:Protease Inhibitors; D053491:Proteinase Inhibitory Proteins, Secretory; D029607:Seminal Vesicle Secretory Proteins; C424482:seminal vesicle-specific antigen; D017430:Prostate-Specific Antigen