Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

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.

Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design

“…72,78 We tested the effect of several peripherally administered peptides described here, including PG-934, SBL-MC-31, SBL-MC-69, SBL-MC-93, and SBL-MC-94 on food intake (data not shown). Despite featuring the previously described favorable Pro 6 , shown to stabilize the macrocyclic ring in solution, 79 none of the assayed peptides affected food intake when administered by the intraperitoneal route.…”

“…As reported by others, SHU9119 only affected food intake when administered centrally, although some SHU9119 -derived peptides such as PG-932 and TCMCB07 show activity when administered peripherally. , We tested the effect of several peripherally administered peptides described here, including PG-934 , SBL-MC-31 , SBL-MC-69 , SBL-MC-93 , and SBL-MC-94 on food intake (data not shown). Despite featuring the previously described favorable Pro 6 , shown to stabilize the macrocyclic ring in solution, none of the assayed peptides affected food intake when administered by the intraperitoneal route.…”

Modulation of Canine Melanocortin-3 and -4 Receptors by Melanocortin-2 Receptor Accessory Protein 1 and 2

“…In this study, we cloned canine MC3R and investigated its pharmacological properties. We have reported cMC4R pharmacology previously [ 54 , 61 ]. In the current study, we also identified a MRAP2 variant, MRAP2b .…”

Safety of TCMCB07, a melanocortin‐4 antagonist peptide, in dogs with naturally occurring cachexia

“…TCMCB07, with the structure Ac‐Nle‐cyclo[Asp‐Pro‐DNal(2′)‐Arg‐Trp‐Lys]‐DVal‐DPro‐NH 2 , is a cyclic substituted melanocortin antagonist 13 which successfully treats cachexia in rodent models of cachexia 14 . The MCR4 in dogs is fully functional, 15 and TCMCB07 is a potent antagonist at the rat, human, and canine MC3 and MC4 receptors in terms of receptor binding and antagonism of cAMP activation by the α‐MSH analogue [Nle 4 , DPhe 7 ]‐MSH (NDP‐MSH; Melanotan‐Ι) 16 . In addition, the pharmacokinetics and safety of TCMCB07 in normal beagle dogs are established 11 .…”

“…14 The MCR4 in dogs is fully functional, 15 and TCMCB07 is a potent antagonist at the rat, human, and canine MC3 and MC4 receptors in terms of receptor binding and antagonism of cAMP activation by the α-MSH analogue [Nle 4 , DPhe 7 ]-MSH (NDP-MSH; Melanotan-Ι). 16 In addition, the pharmacokinetics and safety of TCMCB07 in normal beagle dogs are established. 11 However, further studies are necessary to expand our knowledge of TCMCB07 in a real-world model of naturally occurring disease.…”