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

分子发现处于化学生物学的前沿，创造了可应用于药物化学和药物发现研究的粘合剂。虽然蛋白质具有很高的亲和力和特异性，在自然界中几乎是通用的结合剂，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一个缺点。相比之下，小分子和基于D-氨基酸的多肽在合成方面提供了极端的控制和对蛋白酶的抵抗力，但它们的小尺寸和灵活性会阻碍与目标的亲和力并限制其特异性。在这个项目中，我们旨在结合这两个系统的特点，开发一个计算和实验平台来设计和筛选稳定的D-氨基酸基的小蛋白作为定制结合蛋白(D-novo微型结合蛋白)。该项目将结合小蛋白(40-60个残基)和结合界面的计算从头设计与高通量多肽合成和表征。学生将学习如何分析和操纵Rosetta建模套件中的结构，以及如何合成、纯化和表征多肽和蛋白质。我们的目标是开发一种快速而强大的计算和实验流水线，用于设计可能代表下一代疗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.