Oral Peptide Conjugate to Treat Congestive Heart Failure

口服肽缀合物治疗充血性心力衰竭

• 批准号: 6690400
• 负责人: KENNETH D JAMES
• 金额: $ 10万
• 依托单位: NOBEX CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690400
• 关键词: biotherapeutic agent; cardiovascular agents; chemical conjugate; congestive heart failure; drug design /synthesis /production; endopeptidases; laboratory mouse; oral administration; peptide chemical synthesis; peptides; pharmacokinetics; protein structure

DESCRIPTION (provided by applicant): Congestive heart failure is the only cardiovascular disease that is increasing in prevalence. It is a common cause of death, is accompanied by high indirect costs for treatment, and has a low survival rate upon its onset. The long term goal of this proposal is to develop an orally available drug based on an endogenous peptide to be useful in the treatment of congestive heart failure (CHF). The proposal suggests that a conjugated hBNP may be able to induce the cardiovascular, renal, and endocrine effects that are associated with the native peptide. The most notable advantage of dosing an hBNP conjugate over the native peptide is oral delivery. Covalent attachment of amphiphilic oligomers affords protection from degradative enzymes and facilitates delivery into systemic circulation through the gut wall. The specific aims of this proposal are to synthesize hBNP amphiphilic polymer conjugates, test the conjugates for agonist activity at the human natriuretic peptide receptor A (NPR-A) in vitro, test the conjugates for increased resistance to proteases, and test the conjugates for oral bioavailability in mice. We propose that an oral hBNP conjugate will expand the utilization of this therapeutic to individuals suffering from early stage to overt CHF. Furthermore, an oral hBNP conjugate, by preventing progression from early stage heart failure to more severe phases, may significantly reduce medical costs associated with the treatment of CHF. This Phase I proposal describes a strategy testing three classes of oligomers in order to find the optimal conjugate. Phase II studies will involve pharmacokinetic and pharmacodynamic studies of the most promising candidates arising from Phase I studies.

描述（由申请人提供）：充血性心力衰竭是唯一患病率增加的心血管疾病。它是一个普遍的死亡原因，伴随着高间接治疗费用，并且发作后的存活率较低。该提案的长期目标是开发基于内源性肽的口服药物，可用于治疗充血性心力衰竭（CHF）。该提案表明，共轭HBNP可能能够诱导与天然肽相关的心血管，肾脏和内分泌作用。给予HBNP偶联物比天然肽的最显着优势是口服递送。两亲寡聚的共价附着可保护降解酶，并促进通过肠壁传递到系统性循环中。该提案的具体目的是合成HBNP AmphipHilic聚合物共轭物，测试与人纳特里二酸肽受体A（NPR-A）在体外测试激动剂活性的结合物，测试偶联物以增加对蛋白酶的耐药性，并测试对蛋白酶的耐药性，并测试Oral Bioavavaves oral Bioavavaves obal Bioavavavalesibalsibalsibalsibalsibalsibalsibalsibalsibalsibalsibalsibalsibalsions insiCeS ins cons consMiceS consMiceS insMice insMice insMice insMice insMiceS。我们建议口服HBNP共轭物将这种治疗方法扩展到患有早期阶段到明显CHF的人。此外，通过防止早期心力衰竭到更严重的阶段的进展，口服HBNP共轭物可能会大大降低与CHF治疗相关的医疗费用。 该阶段提出的建议描述了一种策略测试三类的低聚物，以找到最佳的共轭物。第二阶段的研究将涉及I期研究最有前途的候选者的药代动力学和药效学研究。

项目成果

Amphiphilic conjugates of human brain natriuretic peptide designed for oral delivery: in vitro activity screening.

设计用于口服递送的人脑利尿钠肽的两亲性缀合物：体外活性筛选。

• DOI: 10.1021/bc0501000
• 发表时间: 2006
• 期刊: Bioconjugate chemistry.
• 作者: Miller,MarkA;Malkar,NavdeepB;Severynse-Stevens,Diana;Yarbrough,KevinG;Bednarcik,MarkJ;Dugdell,RobertE;Puskas,MonicaE;Krishnan,Radha;James,KennethD
• 通讯作者: James,KennethD