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Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides
Kenneth A Gruber1,2, Ren-Lai Ji3, Fabio Gallazzi4
1John M. Dalton Cardiovascular Research Center, and Department of Medical Pharmacology & Physiology, University of Missouri, Columbia, Missouri 65211, United States.
Abstract:
During the development of a melanocortin (MC) peptide drug to treat the condition of cachexia (a hypermetabolic state producing lean body mass wasting), we were confronted with the need for peptide transport across the blood-brain barrier (BBB): the MC-4 receptors (MC4Rs) for metabolic rate control are located in the hypothalamus, i.e., behind the BBB. Using the term "peptides with BBB transport", we screened the medical literature like a peptide library. This revealed numerous "hits"-peptides with BBB transport and/or oral activity. We noted several features common to most peptides in this class, including a dipeptide sequence of nonpolar residues, primary structure cyclization (whole or partial), and a Pro-aromatic motif usually within the cyclized region. Based on this, we designed an MC4R antagonist peptide, TCMCB07, that successfully treated many forms of cachexia. As part of our pharmacokinetic characterization of TCMCB07, we discovered that hepatobiliary extraction from blood accounted for a majority of the circulating peptide's excretion. Further screening of the literature revealed that TCMCB07 is a member of a long-forgotten peptide class, showing active transport by a multi-specific bile salt carrier. Bile salt transport peptides have predictable pharmacokinetics, including BBB transport, but rapid hepatic clearance inhibited their development as drugs. TCMCB07 shares the general characteristics of the bile salt peptide class but with a much longer half-life of hours, not minutes. A change in its C-terminal amino acid sequence slows hepatic clearance. This modification is transferable to other peptides in this class, suggesting a platform approach for producing drug-like peptides.
Insights
Researchers developed TCMCB07, a peptide drug for cachexia, by identifying common features of blood-brain barrier (BBB) transporting peptides. This peptide utilizes bile salt carriers for transport and has a modified structure for extended drug efficacy.
Area of Science:
- Pharmacology
- Neuroscience
- Drug Development
Background:
- Cachexia involves lean body mass wasting due to hypermetabolic states.
- Melanocortin-4 receptors (MC4Rs) in the hypothalamus control metabolic rate but are behind the blood-brain barrier (BBB).
- Effective drug delivery to the hypothalamus requires crossing the BBB.
Purpose of the Study:
- To design a peptide drug capable of crossing the BBB to treat cachexia.
- To characterize the pharmacokinetic properties of the novel peptide TCMCB07.
- To identify a platform for developing drug-like peptides with improved pharmacokinetic profiles.
Main Methods:
- Literature screening for peptides with BBB transport properties.
- Design and synthesis of an MC4R antagonist peptide (TCMCB07).
- Pharmacokinetic characterization of TCMCB07, focusing on excretion pathways and half-life.
- Identification of TCMCB07's transport mechanism via bile salt carriers.
Main Results:
- Identified common structural features of BBB-transporting peptides: dipeptide of nonpolar residues, cyclization, and Pro-aromatic motif.
- Designed and developed TCMCB07, an effective MC4R antagonist for cachexia treatment.
- Discovered TCMCB07 utilizes hepatobiliary extraction for excretion, a characteristic of bile salt transport peptides.
- Modified TCMCB07's C-terminus to significantly slow hepatic clearance, extending its half-life from minutes to hours.
- Demonstrated that this C-terminal modification is transferable to other peptides in this class.
Conclusions:
- TCMCB07 successfully treats cachexia by targeting hypothalamic MC4Rs via BBB transport.
- TCMCB07 belongs to a class of peptides actively transported by bile salt carriers.
- A C-terminal modification strategy can overcome rapid hepatic clearance, enabling the development of drug-like peptides with predictable pharmacokinetics and BBB transport.
- This represents a potential platform for developing new peptide therapeutics.
