Author information

¹Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.

²NewCures, Innovation and Ventures Office, Northwestern University, Evanston, Illinois 60208, United States.

³Feinberg Medical School, Northwestern University, Chicago, Illinois 60611, United States.

⁴Department of Anesthesiology, Northwestern University, Chicago, Illinois 60611, United States.

⁵The Florey,Parkville, Victoria 3010, Australia.

⁶Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia.

⁷Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 5FB, U.K.

⁸Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands B15 2TT, U.K.

⁹Department of Medicine Division of Nephrology and Hypertension, Chicago, Illinois 60611, United States.

¹⁰Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208, United States.

¹¹Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States.

¹²Department of Pharmacology, Northwestern University, Chicago, Illinois 60611, United States.

¹³International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.

¹⁴Simpson-Querrey Institute, Northwestern University, Chicago, Illinois 60611, United States.

¹⁵Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States.

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.