Oral Delivery of Thrombostatin

描述（由申请人提供）：该提案的假设是胃肠道中的二肽或三肽转运蛋白可用作体内吸收口服递送的肽作为治疗剂的手段。最近的信息表明，血管紧张素转化酶的缓激肽分解产物，五肽Arg-Pro-Pro-Gly-Phe（RPPGF），我们将其命名为“Thrombostatin TM”，具有与蛋白酶激活受体1（PAR 1）的细胞外片段（凝血酶受体）相互作用的能力，以防止凝血酶裂解和激活。目前的研究将确定这些抗凝血酶肽是否可以口服吸收成为体内活性凝血酶抑制剂。这项建议的具体目标如下： 具体目标1：评估Thrombostatin TM衍生物在肠液中的化学和酶稳定性，以产生更稳定的、具有更高抑制活性的口服可吸收化合物。 具体目标2：研究将确定在大鼠中是否存在这些凝血酶抑制肽的口服吸收以作为血小板凝血酶活化的抑制剂。 这些调查有两个目的。首先，将进行研究以确定可从胃肠道吸收的RPPGF衍生物的最稳定形式。其次，将进行研究以确定RPPGF衍生物的口服吸收是否抑制血小板的凝血酶活化。这些研究旨在开发一种口服形式的血小板选择性凝血酶抑制剂。这样的药剂将可用于管理急性冠状动脉综合征和其他血栓形成病症。

DESCRIPTION (provided by applicant): The hypothesis of this proposal is that the di- or tri-peptide transporter in the gastrointestinal tract can be used as a means to absorb orally delivered peptides as therapeutics in vivo. Recent information indicates that the bradykinin breakdown product of angiotensin converting enzyme, the pentapeptide Arg-Pro-Pro-Gly-Phe (RPPGF), which we have named "Thrombostatin TM'' has the ability to interact with the extracellular fragment of protease activated receptor 1 (PAR1), the thrombin receptor, to prevent thrombin cleavage and activation. Investigations presently will determine if these anti-thrombin peptides can be orally adsorbed to be active thrombin inhibitors in vivo. The specific aims of this proposal are as follows: Specific aim #1: Evaluate the chemical and enzymatic stability of Thrombostatin TM derivatives in intestinal fluids to create more stable, orally absorbable compounds with increased inhibitory activity. Specific aim #2: Investigations will determine in rats if there is oral absorption of these thrombin inhibitory peptides to act as inhibitors of thrombin activation of platelets. The purpose of these investigations is two-fold. First, investigations will be performed to determine the most stable forms of the RPPGF derivatives that can be absorbed from the gastrointestinal tract. Second, studies will be performed to determine if oral absorption of RPPGF derivatives inhibit thrombin activation of platelets. These investigations aim to develop an oral form of a platelet-selective thrombin inhibitor. Such an agent will be useful in the management of acute coronary syndromes and other disorders of thrombosis.