Selective targeting of matrix metalloproteinases for developing preterm labor therapeutics

选择性靶向基质金属蛋白酶用于开发早产疗法

基本信息

批准号：
10509786
负责人：
Maryam Raeeszadeh Sarmazdeh
金额：
$ 21.12万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10509786
关键词：
ART protein Address Affinity Binding Biochemical Biological Assay Birth Cell physiology Data Directed Molecular Evolution Dose Engineering Enzymes Family Foundations Future Gelatinase A Gelatinase B Goals Human Infant Mortality Infection Inflammatory Inhibition of Matrix Metalloproteinases Pathway Intervention Lead Libraries Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mechanics Mission Mus Myometrial National Institute of Child Health and Human Development Oxytocin Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pregnancy Outcome Pregnant Uterus Premature Birth Premature Labor Process Production Protein Engineering Proteins Public Health Recombinants Research Research Priority Role Scaffolding Protein Smooth Muscle Surface Techniques Testing Therapeutic Therapeutic Agents Tissue Engineering Tissue Inhibitor of Metalloproteinases Tissues Tocolysis Tocolytic Agents Toxic effect United States Uterine Contraction Uterus Variant Woman Yeasts base cervical remodeling combinatorial drug candidate drug testing experimental study health disparity human tissue improved in vivo in vivo Model inhibitor member myometrium novel overexpression perinatal health pre-clinical premature prevent response screening side effect therapeutic protein therapeutic target

项目摘要

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.

项目摘要/摘要我们已经表明，基质金属蛋白酶家族（MMP-2和MMP-9）的特定成员是过度表达了早产的肌层，这些酶加剧了收缩反应人子宫平滑肌。因此，MMP-2/9可以用作阻止早产的治疗靶标。金属蛋白酶（TIMP）的组织抑制剂是具有亚洋摩尔亲和力的内源性MMP抑制剂。考虑MMP在细胞功能中的多方面作用，我们旨在靶向特定的MMP（MMP-2/9），负责早产患者的子宫收缩，具有高选择性的同时避免与其他有益MMP的相互作用。我们的中心假设是基于TIMP蛋白的选择性可以开发治疗剂来促进子宫静止。我们将使用蛋白质工程技术例如，基于TIMP蛋白支架的定向进化来生产溶剂药物候选者以治疗早产劳动。在AIM 1中，我们将使用定向的进化和酵母表面显示到基于TIMP的蛋白质脚手架以提高对MMP-2/9的结合选择性。在AIM 2中，我们将评估野生型的能力和设计的TIMP减少人子宫组织的收缩。这些数据有望很重要因为它们将为临床前体内早产模型中的候选药物测试提供基础劳动。