Gruber, K. A. | bioRxiv Science

bioRxiv2024

Melanocortin-4 receptor antagonist TCMCB07 alleviates chemotherapy-induced anorexia and weight loss

Cancer patients undergoing chemotherapy often experience anorexia and weight loss that significantly deteriorates overall health, reduces treatment tolerance and quality of life, and worsens oncologic outcomes. There are currently few effective therapeutic options to mitigate these side effects. The central melanocortin system, which plays a pivotal role in regulating appetite and energy homeostasis, presents a logical target for treating anorexia and weight loss. In this preclinical study, we evaluated the efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor, in mitigating anorexia and weight loss in several rat models of chemotherapy: cisplatin, 5-fluorouracil, cyclophosphamide, vincristine, doxorubicin, and a combination of irinotecan and 5-fluorouracil. Our results indicate that peripheral administration of TCMCB07 improved appetite, stabilized body weight, preserved fat and heart mass, and slightly protected lean mass after multiple cycles of chemotherapy. Furthermore, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced treatment effectiveness. Similar effects from TCMCB07 treatment were observed in a rat tumor model following combination chemotherapy. No significant adverse effects nor increased chemotherapy-related toxicities were observed with TCMCB07 treatment. These findings suggest that peripheral administration of TCMCB07 holds promise as a therapeutic approach for alleviating chemotherapy-induced anorexia and weight loss, potentially benefiting numerous patients undergoing chemotherapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/613069v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@cbe32borg.highwire.dtl.DTLVardef@1af55e7org.highwire.dtl.DTLVardef@30deb1org.highwire.dtl.DTLVardef@6c39a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Vector-Mediated Transport Producing Drug-like Peptides

Drugs that are structural mimetics of peptides (e.g. small molecules) have been plagued by problems associated with oral availability and transcellular movement. Vector-mediated transport, where a potentially therapeutic drug is covalently linked to another molecule that is a ligand for an active transport or transcytosis system, was developed as an approach for moving a drug across the blood-brain-barrier. We now report a vector approach that produced peptides with oral activity, blood-brain-barrier transport, and extended in vivo half-life. Generating these properties requires secondary structure stabilization into a {beta} hairpin, and the addition of a C-terminal dipeptide sequence composed of non-polar residues. Peptides with biological activity incompatible with these derivatizations were covalently linked to a model transport vector, producing a chimera with the therapeutic activity of the peptide and the transport properties of the vector. Our platform technology may be a general approach for the design of drug-like peptides.

pharmacology and toxicology↗