D-novo minibinders: developing a high throughput platform for computational design and production of tailored synthetic proteins

分子发现是化学生物学的前沿，它创造了可以应用于药物化学和药物发现研究的粘合剂。虽然蛋白质具有高亲和力和特异性，并且在自然界中几乎是通用的结合物，但它们的大小，免疫原性和低稳定性可能是开发诊断和治疗的缺点。相比之下，小分子和基于d -氨基酸的肽在合成方面提供了极端的控制和对蛋白酶的抗性，但它们的小尺寸和灵活性会阻碍对靶标的亲和力并限制它们的特异性。在这个项目中，我们的目标是结合这两个系统的特点，并开发一个计算和实验平台，用于设计和筛选稳定的d -氨基酸基微型蛋白作为定制粘合剂（D-novo微型粘合剂）。该项目将结合微型蛋白（40-60个残基）和结合界面的计算从头设计与高通量肽合成和表征。学生将学习如何分析和操纵结构在罗塞塔建模套件和合成，纯化和表征肽和蛋白质。我们的目标是开发一种快速和强大的计算和实验管道，用于设计可能代表下一代治疗方法的新型合成粘合剂。

Molecular discovery is at the forefront of chemical biology creating binders that can be applied in medicinal chemistry and drug discovery research. While proteins reach high affinity and specificity and act as almost universal binders in Nature, their size, immunogenicity and low stability can represent a drawback in developing diagnostics and therapeutics. Small molecules and D-amino acid - based peptides, in contrast, provide extreme control on the synthesis side and resistance to proteases, but their small size and flexibility can hinder the affinity to the target and limit their specificity.In this project we aim to combine the features of both systems and develop a computational and experimental platform for design and screening of stable D-amino acid based miniproteins as tailored binders (D-novo minibinders). This project will combine computational de novo design of miniprotein (40-60 residues) and binding interfaces with high throughput peptide synthesis and characterization. The student will learn how to analyze and manipulate structure in the Rosetta modelling suite and to synthesize, purify and characterize peptides and proteins.Our aim is to develop a rapid and robust computational and experimental pipeline for design of novel synthetic binders that might represent the next generation of therapeutics.