Berger Or, Choi Wonmin, Ko Caroline H, Thompson Matthew P, Avram Michael J, Scott Daniel J, Hoare Bradley L, Cridge Riley, Wheatley Mark, Bathgate Ross A D, Batlle Daniel, Gianneschi Nathan C
Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
NewCures, Innovation and Ventures Office, Northwestern University, Evanston, Illinois 60208, United States.
ACS Pharmacol Transl Sci. 2024 Apr 30;7(5):1252-1261. doi: 10.1021/acsptsci.3c00305. eCollection 2024 May 10.
Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease first reported over a century ago, but its management still poses an unmet challenge. A therapeutic agent found to stabilize the condition is a short cyclic peptide, vasopressin analogue, terlipressin (TP). While TP is commonly prescribed for HRS patients in most parts of the world, it was only recently approved for use in the United States. TP exhibits short circulation half-lives and adverse side effects associated with the dose required. Herein, we present a 1,18-octadecanedioic acid (ODDA) conjugate of the cyclic peptide (ODDA-TP), which enables noncovalent binding to serum albumin native fatty acid binding modes. ODDA-TP is demonstrated to outperform TP alone in studies including cellular receptor activation, stability in plasma, pharmacokinetics, and performance in rats. Specifically, ODDA-TP had an elimination half-life 20 times that of TP alone while exhibiting a superior safety profile.
肝肾综合征（HRS）是一种终末期肝病的危及生命的并发症，早在一个多世纪前就有报道，但对其治疗仍然是一个尚未解决的挑战。一种被发现能稳定病情的治疗药物是一种短环肽、血管加压素类似物特利加压素（TP）。虽然在世界大部分地区，TP通常被开给HRS患者，但它直到最近才在美国被批准使用。TP具有较短的循环半衰期以及与所需剂量相关的副作用。在此，我们展示了一种环肽的1,18-十八烷二酸（ODDA）缀合物（ODDA-TP），它能够以天然脂肪酸结合模式与血清白蛋白进行非共价结合。在包括细胞受体激活、血浆稳定性、药代动力学以及在大鼠体内的表现等研究中，ODDA-TP被证明优于单独使用的TP。具体而言，ODDA-TP的消除半衰期是单独使用TP的20倍，同时表现出更优的安全性。
