Melanocortin analogs having enhanced activity and transport
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9534018-B2
Publication Date
2017-01-03
Expiration Date
Abstract
Described herein are melanocortin analogs having enhanced activity and transport.
Core Innovation
The disclosure describes non-naturally occurring melanocortin analogs engineered to enhance melanocortin activity and to improve trans-epithelial transport and blood-brain barrier penetration while minimizing cardiovascular and other side effects. The design centers on melanocortin pharmacophores containing cation–π motifs and “overlapping pharmacophores,” and the analogs are configured to support epithelium membrane traversal and blood-brain barrier membrane traversal.
The document describes degradation-resistant N- and/or C-terminal di-/tri-peptide extensions as transporter-compatible carriers while stabilizing the RFamide-related motif. It further describes stereospecificity concepts using D- and L-amino acids and positional concepts related to β/α-carbon, together with multiple formula-based peptide designs with variable residue sets, including N-terminal acylation and C-terminal amidation.
The melanocortin analogs may be cyclized through moieties including disulfide bonds and lactam bridges, including side-chain lactam bridges. The patent provides multiple example constructs, including TCMCB01–TCMCB07 and related constructs, and describes comparisons among transporter-compatible stereospecific embodiments for BBB and oral/GI activity. Extensive mechanistic and in vivo support is provided, including cardiovascular effects and anti-cachexia and feeding/weight outcomes.
The disclosure also describes effects in LPS-induced cachexia models, including behavioral and physiological changes such as restored behavior after melanocortin peptide treatment. It discusses cachexia-associated phenotypes including anorexia and lethargy, melanocortin receptor-targeting peptide classes including melanocortin 3/4 receptor antagonists and a melanocortin 5 agonist, and melanocortin 3/4 agonists in the context of reducing excess body weight.
Claims Coverage
The provided excerpt includes multiple independent claims. Across these claims, the inventive features focus on a metabolically stable, cyclized melanocortin-analog framework with specified residue constraints plus N-terminus acylation and C-terminus amidation that traverses epithelium membranes and/or blood-brain barrier membranes, and membership of the analog in one of multiple specified non-naturally occurring sequence embodiments.
Metabolically stable analog with epithelium and/or BBB traversal
A non-naturally occurring melanocortin analog comprising a metabolically stable C-terminal extension that minimizes or reduces side effects and that facilitates traversal of epithelium membranes, blood-brain barrier membranes, or both membranes, comprising the sequence according to Formula I with defined residue selections, cyclization constraints, acylated N-terminus, and amidated C-terminus modifications.
Specified non-naturally occurring sequence embodiments
A non-naturally occurring melanocortin analog comprising any one of the sequences of SEQ ID NOs: 21, 30, 31, 32, 33, 66, 67, 68, 69, 90, 91, 92, 93, 118, 119, 120, 121, 154, 155, 156, 157, 178, 179, 180 or 181.
Formula I residue framework with cyclization constraints
A sequence according to Formula I with defined selections for residues X1, X2, X3, R1–R7, and Y1–Y3, including specific cases for absence or presence depending on whether R2 is an n-pentanoyl or n-hexanoyl group, and wherein the melanocortin analog is cyclized through a moiety selected from the listed disulfide bond or lactam bridge or closure options linking specified residue positions.
N-terminus acylation and C-terminus amidation
The N-terminus is modified by acylation, and the C-terminus is modified by amidation.
Taken together, the claim set provided in the excerpt covers non-naturally occurring melanocortin analogs defined either by a metabolically stable, epithelium-/BBB-traversing Formula I residue framework with cyclization plus N-terminus acylation and C-terminus amidation, or by specific enumerated sequence embodiments via listed SEQ ID NOs.
Stated Advantages
Minimizes or reduces side effects.
Documented Applications
Cardiovascular effects, including cardiac arrhythmias and ECG/MAP/HR outcomes.
Anti-cachexia activity, including in a Lewis sarcoma model and in LPS-induced cachexia.
Feeding/weight outcomes, including effects related to cachexia/anorexia/lethargy.
Oral/GI activity and blood-brain barrier transport / epithelium membrane traversal.
Treatment of cachexia via a kit context that includes containers with a pharmaceutical composition, a device for administering it, a reagent for diluting it, and instructions for use.
Reduction of excess body weight.
Appetite, lean mass wasting, and exocrine secretion disorders.
Interested in licensing this patent?