Selective targeting of matrix metalloproteinases for developing preterm labor therapeutics

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT We have shown that specific members of the matrix metalloproteinase family (MMP-2 and MMP-9) are overexpressed in preterm laboring myometrium and that these enzymes exacerbate contractile responses in human uterine smooth muscle. Therefore, MMP-2/9 may serve as therapeutic targets to block preterm labor. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors with subnanomolar affinity. Considering multifaceted role of MMPs in cellular function, we aim to target specific MMPs (MMP-2/9), responsible for uterine contraction in patients with preterm labor, with high selectivity while avoiding interactions with other beneficial MMPs. Our central hypothesis is that selective TIMP protein-based therapeutics can be developed to promote uterine quiescence. We will use protein engineering techniques such as directed evolution to produce tocolytic drug candidates based on TIMP protein scaffold to treat preterm labor. In Aim 1, we will use directed evolution and yeast surface display to engineer TIMP-based protein scaffolds to improve binding selectivity toward MMP-2/9. In Aim 2, we will evaluate the ability of wild-type and engineered TIMPs to reduce contractions in human uterine tissue. These data are expected to be significant because they will provide the foundation for candidate drug testing in preclinical in vivo models of preterm labor.