MENTSH analogs as therapeutics for diabetes, obesity, and their associated diseases and complications

Inventors

Cohen, Pinchas • Yen, Kelvin

Assignees

University of Southern California USC

Abstract

Described herein is a novel, mitochondrial encoded, open reading frame, that leads to the production of a new mitochondrial peptide. Residing within the ND-Two subunit, a specific small nucleotide polymorphism disrupts expression of this mitochondrial peptide, and is correlated with an increase in obesity and diabetes, particularly in certain ethnic populations. In vitro administration of the peptide increases insulin secretion, decreases fat accumulation and improves glucose uptake in muscle cell. Antibodies generated against the peptide can be used for detecting peptide deficiency, in addition to SNP detection, supporting diagnostic approaches. In vivo studies further revealed that administration of the peptide improves glucose tolerance, thereby providing a new therapeutic avenue for a novel diabetes therapy and decreases bodyweight, thus serving as a novel obesity therapy. Generation of synthetic analogs further enhance or abrogated activity relative to the natural peptide.

Core Innovation

The mitochondrial-derived peptide encoded in the ND2/ND-Two subunit, denoted MENTSH, is described as a mitochondrial sORF product. A SNP, Rs28357981 (MitoT4978C; ATT→ACT start-codon disruption), is described as disrupting expression of the mitochondrial sORF product. The disruption correlates with increased diabetes/obesity risk in certain ethnic groups, including Hispanic. The peptide is described as SEQ ID NO:97 (MKPNPATQNLSMLLNYPH).

MENTSH is described as increasing insulin secretion and reducing fat accumulation. The peptide is also described as activating Akt signaling in a cell-specific manner, improving glucose uptake and glucose tolerance, and decreasing weight gain under high-fat diet conditions. Additional described effects include alterations in metabolomics consistent with increased fat utilization.

The document also describes synthetic MENTSH analogs that can enhance or abrogate activity. The peptide and/or SNP-associated biomarker concepts are described as supporting detection and diagnostics, including ELISA for peptide detection and antibodies related to detecting deficiency. Pharmaceutical embodiments are described for short mitochondrial peptides (14–24 aa) with sequence identity thresholds to SEQ ID NO:97 and possible post-translational/artificial modifications.

Claims Coverage

The identified independent claims cover compositions comprising a MENTSH peptide defined by sequence identity to SEQ ID NO:97, with additional limitations on peptide length and, in certain claims, enumerated sequence options, negatively charged substitutions at specific relative positions, and post-translational/artificial modifications. Across the independent claims, inventive features include sequence-identity-defined peptide compositions, short fixed-length variants, specific negative-charge substitution patterns, and composition embodiments incorporating named modification types.

Overall, the claims cover MENTSH peptide compositions defined by at least 70% sequence identity to SEQ ID NO:97, including short fixed-length (16 amino acid) embodiments. Certain claim scopes further require negatively charged substitutions at positions relative to SEQ ID NO:97 (serine-11 and tyrosine-16), with at least one substitution being aspartic acid.

Stated Advantages

Documented Applications