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

这个小企业创新研究（SBIR）一期项目将推进一种创新药物发现技术，以解决蛋白质-蛋白质相互作用等重要疾病靶点。传统的药物发现技术很少能成功地识别出能够破坏蛋白质之间相互作用的药物。虽然多肽可以破坏蛋白质之间的相互作用，但它很少能制造出好的药物。这项提议描述了一种将肽转化为药物样分子的有效方法。表征良好且重要的抗癌靶点p53-hdm2将被用作模型系统。文献中已经描述了p53-hdm2相互作用的肽抑制剂。第一阶段的目标是将这些肽转化为药物样分子。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。这项研究的更广泛的影响是开发技术来解决当前药物发现方法无法解决的重要人类疾病目标。蛋白质之间的相互作用是开发新疗法的最大的未开发机会之一。该技术提供了一种通用和系统的方法，通过有效地将肽转化为小分子来解决这类目标。它有可能彻底改变药物发现过程，因此商业机会是巨大的。此外，所提出的技术将促进我们对药物发现的理解。社会影响将是巨大的，因为这项技术将有助于发现药物，以满足未满足的医疗需求。

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.