SBIR Phase I: A new drug discovery method to transform peptides to small molecules: proof of principle with p53-hdm2

这个小型企业创新研究(SBIR)第一阶段项目将推进一项创新的药物发现技术，以解决蛋白质-蛋白质相互作用等重要疾病目标。传统的药物发现技术很少成功地识别出可以破坏蛋白质-蛋白质相互作用的药物。虽然多肽可以破坏蛋白质之间的相互作用，但多肽很少能成为好的药物。这项提议描述了一种将多肽转化为类药物分子的强大方法。具有良好特性和重要的抗癌靶点P53-Hdm2将被用作模型系统。文献中已经描述了P53-Hdm2相互作用的多肽抑制剂。这一第一阶段提案的目标是将这些多肽转化为类药物分子。随后，这些分子可以进一步发展成为治疗人类癌症的候选药物。此外，拟议研究的成功完成将验证一种变革性的新药发现技术。这项研究的更广泛影响是开发技术，以解决目前药物发现方法不适用的重要人类疾病靶点。蛋白质-蛋白质相互作用是开发新疗法的最大尚未开发的机会之一。该技术通过有效地将多肽转化为小分子，提供了一种通用而系统的方法来解决这一目标类别。它有可能给药物发现过程带来革命性的变化，因此商业机会是巨大的。此外，拟议的技术将促进我们对药物发现的理解。这将产生巨大的社会影响，因为这项技术将促进发现满足未得到满足的医疗需求的药物。

This Small Business Innovation Research (SBIR) Phase I project will advance an innovative drug discovery technology to tackle important disease targets such as protein-protein interactions. Conventional drug discovery technologies are rarely successful at identifying drugs that can disrupt protein-protein interactions. While peptides can disrupt protein-protein interactions, peptides seldom make good drugs. This proposal describes a powerful approach to transform peptides into drug-like molecules. The well-characterized and important anti-cancer target p53-hdm2 will be used as a model system. Peptide inhibitors of the p53-hdm2 interaction have been described in the literature. The objective of this Phase I proposal is to convert these peptides into drug-like molecules. Subsequently, these molecules can be further advanced into drug candidates for treating human cancers. In addition, successful completion of the proposed research will validate a transformative new drug discovery technology.The broader impacts of this research are to develop the technologies to tackle important human disease targets that are not amenable to current drug-discovery approaches. Protein-protein interactions present one of the largest untapped opportunities to develop new therapies. The technology provides a general and systematic method to tackle this target class by efficiently transforming peptides into small molecules. It has the potential to revolutionize the drug discovery process, and thus the commercial opportunity is enormous. In addition, the proposed technology will advance our understanding of drug discovery. The societal impact will be substantial, as the technology will facilitate the discovery of drugs for unmet medical needs.