Releasable site-specific attachment of macromolecules to therapeutic peptides

描述（由申请人提供）：许多有效的和特定的肽遭受短期或次优持续时间的问题。解决这些问题的一种可能的方法是与大分子结合，如聚乙二醇（PEG），这种大分子会慢慢从体内排出，从而延长附着肽的作用。对于多肽治疗，通常必须将未改变的药物从大分子中释放出来，并在适当的时间内满足需要。目前的方法通常使用可切割连接体将肽连接到大分子上，这种连接体由于酶或生理环境的作用而切割。虽然这种方法通常是成功的，但它们通常不能预测或控制药物释放的速度，从而不能控制作用的持续时间。该项目的目标是a)开发一种新的平台技术，允许大分子附着在肽上的位点特异性，b)开发可预测的、化学控制的肽释放技术。如果成功，a)我们将开发出可广泛应用的大分子多肽控制释放的通用技术，并为未来将此类技术应用于治疗性多肽奠定基础。

DESCRIPTION (provided by applicant): Many potent and specific peptides suffer problems of short or sub-optimal duration. A possible solution to such problems involves conjugation to macromolecules such as polyethylene glycol (PEG) that are slowly eliminated from the body, and thus prolongs the action of the attached peptide. For peptide therapeutics, it is usually essential that the unchanged drug be released from the macromolecule with timing appropriate to satisfy the need. Current approaches often use cleavable linkers to attach the peptide to the macromolecule by a linker that cleaves because of the effect of an enzyme, or physiological environment. Although such approaches are often successful, they usually do not allow prediction or control of the rate of drug release and hence the duration of action. The objective of this project is a) to develop a novel platform technology that allows site-specific attachment of a macromolecule to peptides, and b) to develop technology for predictable, chemically-controlled release of such peptides. If successful, a) we will have developed general technology for controlled release of peptides from macromolecules that could be broadly applied, and set the stage for future applications of such technology to therapeutic peptides. PUBLIC HEALTH RELEVANCE: We propose to develop a novel platform technology that allows site-specific attachment of macromolecules to peptides, and predictable, controlled release of the native peptides that will allow an increase in the duration of their action. If successful, we will have developed general technology for controlled release of therapeutic peptides from macromolecules that could be broadly applied to the area of therapeutic peptides.