CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies

抗体是由免疫系统产生的。它们能识别外来的传染因子。它们的分子识别能力使它们成为感知和治疗疾病的理想选择。然而，它们在结合和阻断蛋白酶的作用方面是没有用的。这一点很重要，因为蛋白酶的活性可以引发癌症的发展。例如，在癌症和糖尿病的发展过程中，被称为基质金属蛋白酶（MMPs）的与癌症发展有关的关键蛋白酶会过量产生。本项目的目的是评估用独特氨基酸修饰抗体对MMP活性调控的影响。该提案的教育部分旨在加强塔夫茨大学STEM大使计划，并加强与地区职业/技术高中生物技术计划的伙伴关系。细胞外蛋白酶和肽酶在人类健康和疾病中起着关键作用。这些酶的特异性破坏仍然是一个根本性的挑战。例如，基质金属蛋白酶（MMPs）在发育、炎症、癌症和传染病中起着关键作用。高特异性抑制剂对于揭示酶的分子功能和建立具有改善治疗潜力的新一代抑制剂至关重要。总体目标是建立“化学多样化”抗体的原理，使下一代蛋白酶抑制剂的发现成为可能。该项目将评估非规范氨基酸和酵母展示技术的整合，以利用抗体内的共价（不可逆）结合和金属结合功能。研究人员希望发现能够干扰酶功能的化学物质。这些研究还可以确定用例，在抗体中添加化学物质会产生具有常规抗体无法设计的特性（如效力、作用持续时间或特异性表位靶向）的抑制剂。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Antibodies are created by the immune system. They recognize foreign infectious agents. Their molecular recognition capabilities make them ideal to sense and to treat diseases. They are, however, not useful in binding to and blocking the action of proteases. This is important because protease activity can trigger the development of cancers. Key proteases involved in cancer development, called matrix metalloproteases (MMPs), are overproduced during the development of cancer and during diabetes, for example. The objective of this project is to evaluate the impact of modifying antibodies with unique amino acids on the regulation of MMP activity. The education component of this proposal seeks to enhance the Tufts STEM Ambassadors program and strengthen a partnership with the biotechnology program of an area vocational/technical high school.Extracellular proteases and peptidases play key roles in human health and disease. The specific disruption of these enzymes remains a fundamental challenge. For example, matrix metalloproteinases (MMPs) play key roles in development, inflammation, cancer, and infectious disease. Highly specific inhibitors are essential for uncovering the molecular functions of enzymes and for establishing a new generation of inhibitors with improved therapeutic potential. The overall goal is to establish principles of “chemically diversified” antibodies that enable next-generation protease inhibitor discovery. This project will evaluate integration of noncanonical amino acids and yeast display technology to exploit covalent (irreversible) binding and metal binding functionalities within antibodies. The investigators hope to discover chemistries capable of interfering with enzyme functions. These studies could also identify use cases where adding chemistries to antibodies leads to inhibitors with properties (such as potency, duration of action, or specific epitope targeting) that cannot be engineered into conventional antibodies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.