Abstract
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 via native fatty acid binding modes. ODDA-TP is demonstrated to outperform TP alone in studies including in vitro cellular receptor activation, stability in plasma, pharmacokinetics, and performance in vivo in rats. Specifically, ODDA-TP had an elimination half-life 20 times that of TP alone while exhibiting a superior safety profile.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1252-1261 |
| Number of pages | 10 |
| Journal | ACS Pharmacology and Translational Science |
| Volume | 7 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 10 2024 |
Funding
The work presented here made use of (1) The IMSERC NMR and MS facilities at Northwestern University, which have received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), and Northwestern University; and (2) The Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support grant no. P30 CA060553. Work at the Florey Institute was supported by the National Health and Medical Research Council (NHMRC) of Australia project grant nos.1081801 (D.J.S.), 1081844, and 1141034 (D.J.S. and R.A.D.B.), an NHMRC Fellowship (R.A.D.B.), a NHMRC Boosting Dementia Research Leadership Fellowship (to D.J.S.), and the Victorian Government\u2019s Operational Infrastructure Support Program. We thank Sharon Layfield and Tania Ferraro for technical assistance, and we would like to acknowledge the Melbourne Cytometry Platform for assistance with flow cytometry. N.C.G. would like to thank Northwestern University for financial support and for aiding in the study design for the experiments conducted at external CROs (IRBM S.p.A. Pomezia RM, Italy, and WuXi AppTec Co., Ltd. Shanghai, China) through the NewCures Accelerator program.
Keywords
- hepatorenal syndrome
- lipidation
- terlipressin
- therapeutic peptides
ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology