SBIR Phase I: Novel approach to the oral delivery of biologically active peptide analogs

面向公众的项目摘要这个小型企业创新研究(SBIR)第一阶段项目的动机是关于药物分子在人体内处理方式的基本问题。候选药物除非到达人体内的适当部位，然后在这些部位持续存在，否则无法治疗人类疾病。这项拟议中的研究重点是一种特殊的生物活性化合物，称为“肽”。多肽可以在体内以强大和有利的方式发挥作用，具有高度的作用特异性(将“副作用”降至最低)，但它们在给药后很快就会被破坏。多肽的这一弱点要求它们定期注射，但如果可以口服的话，多肽药物会更有用。这项SBIR第一阶段项目研究了独特的类肽分子，这些分子旨在保留多肽本身的良好药理作用，但防止体内迅速破坏多肽的降解机制。胃是多肽最具破坏性的部位，这个项目的目标是产生足够强大的类肽分子，使其能够在胃中存活并到达小肠，在那里它们可以被吸收。实现这些分子设计目标除了推进药物设计外，还具有很高的智力价值。这个项目的更广泛的影响/商业潜力是巨大的。当前基于多肽的药物是人类医疗保健的重要工具，而基于多肽的新药的开发在美国和世界范围内的药物研究工作中所占的比例越来越大。目前几种针对2型糖尿病(T2 DM)和骨质疏松症等普遍疾病的多肽药物的销售额超过10亿美元。这些药物必须以注射的方式运送。如果具有相同健康益处的新药以药丸的形式出现，口服给药的便利性将迅速占领大部分市场。此外，我们的新设计战略带来的高度稳定性将使目前无法解决的疾病药物的开发成为可能。因此，这个项目的商业潜力相当高。目前可注射药物的口服替代品将产生重大的更广泛的影响，因为它们将提高患者的依从性。例如，对T2 DM的治疗不当会导致许多不利的健康后果，降低患者的生产力和生活质量。以药丸形式提供多肽药物的普遍能力导致的依从性增加将极大地改善患者的结局，包括我们当前计划所针对的特定患者群体。

Project Abstract for the general public This Small Business Innovation Research (SBIR) Phase I project is motivated by fundamental questions about the way drug molecules are processed in the human body. Drug candidates cannot address a human disease unless they reach the appropriate sites within the body and then persist in those sites. The proposed research focuses on a particular class of bioactive compounds called "peptides." Peptides can act in powerful and favorable ways within the body, with high specificity of action (which minimizes "side effects"), but they are subject to very rapid destruction after administration. This weakness of peptides requires that they be injected regularly, but peptide drugs would be much more useful if they could be taken orally. This SBIR Phase I project examines unique peptide-like molecules that are designed to retain the favorable pharmaceutical action of peptides themselves but to resist degradation mechanisms within the body that rapidly destroy peptides. The stomach is the most destructive site for peptides, and this project aims to generate peptide-like molecules that are sufficiently robust to survive the stomach and reach the small intestine, where they can be absorbed. Achieving these molecular design goals would have high intellectual merit in addition to advancing drug design. The broader impact/commercial potential of this project is significant. Current peptide-based drugs constitute important tools in human healthcare, and development of new peptide-based drugs represents a growing proportion of the pharmaceutical research effort in the U.S. and worldwide. Several current peptide drugs, addressing widespread diseases such as type 2 diabetes (T2DM) and osteoporosis, have sales in excess of $1 billion. These drugs must be delivered by injection. If new drugs featuring the same health benefits became available in pill form, the convenience of orally delivered drugs would rapidly capture most of the market. Moreover, the high stability engendered by our new design strategy would enable the development of drugs for diseases that currently cannot be addressed. Thus, the commercial potential of this project is quite high. Orally delivered replacements for currently injectable drugs would have a substantial broader impact because they would enhance patient compliance. Inadequate treatment of T2DM for example, leads to many adverse health consequences that degrade productivity and quality of life for patients. Increased compliance resulting from a generalized ability to deliver peptide drugs in pill form would vastly improve outcomes for patients, including the specific patients populations targeted by our current programs.