ZP2 peptide beads select human sperm in vitro, decoy mouse sperm in vivo, and provide reversible contraception

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Science Translational Medicine  27 Apr 2016:
Vol. 8, Issue 336, pp. 336ra60
DOI: 10.1126/scitranslmed.aad9946

Two sides of the same peptide

The zona pellucida, a matrix that surrounds ovulated eggs, is the site of sperm recognition and binding, which precede sperm penetration and fertilization. Avella et al. identified a peptide from the zona pellucida called ZP2, which the authors attached to agarose beads to facilitate infertility treatment or, conversely, contraception. On the one hand, the beads with ZP2 peptide were combined with sperm in vitro to successfully select the best sperm for assisted reproductive technologies. On the other hand, the same beads placed into the uterus of fertile mice bound any incoming sperm and prevented them from reaching the eggs, thus providing a long-acting method of contraception. A related podcast discusses these findings.


Gamete recognition in the female reproductive tract occurs at the surface of the zona pellucida surrounding ovulated eggs. The acellular zona matrix is composed of three (mouse) or four (human) proteins (ZP1 to ZP4), and the amino terminus of ZP2 is the primary sperm-binding ligand. Mouse and human sperm bind, respectively, to recombinant moZP235–149 and huZP239–154 peptides attached to agarose beads. Mouse ZP2 peptide beads markedly inhibited fertilization of ovulated mouse eggs inseminated in vitro and incubated overnight. Similarly, human ZP2 peptide beads prevented sperm binding and penetration of transgenic ZP2Rescue zonae pellucidae, in which human ZP2 replaced mouse ZP2. When mouse ZP2 peptide beads were transcervically deposited into the uterus, there was no change in mating behavior and copulatory plugs were present, but bound sperm did not progress into the oviduct and female mice were infertile. On average, contraception lasted >10 estrus cycles but was reversible with no detectable pathology in the reproductive tract. Despite the long-term contraceptive effect, initial sperm binding to the peptide beads was reversible in vitro. We exploited this observation to select human sperm that were better able to penetrate the zonae of human ZP2Rescue eggs, and the approach holds promise for identifying superior sperm for human assisted reproductive technologies (ART). We conclude that the amino-terminal ZP2 peptide supports sperm binding, which is initially reversible but, with time, becomes irreversible. Short-term, reversible binding may be useful in selecting sperm for ART, and long-term binding decoys sperm and results in effective contraception in mice.

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