Angiotensin (1-7) analogs and methods relating thereto
Inventors
Gallagher, Patricia • TALLANT, ANN • Yohannes, Daniel • Gruber, Kenneth A.
Assignees
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Publication Number
US-10829519-B2
Publication Date
2020-11-10
Expiration Date
Abstract
Angiotensin (1-7) analogs are provided. Also provided are methods of making such analogs methods for using analogs as therapeutic compositions such as, for example, treatment cancer.
Core Innovation
The disclosed invention relates to Ang(1-7) (mas receptor) peptide analogs defined by a compound of the formula R1—Z—R9—Y1, including SEQ ID NO:5, where the scaffold includes a cyclic structure. In the formula, R1 is selected from norleucine (Nle), leucine (L), alanine (A), norvaline (Nva), azidohomoalanine (Aha), or 2-Aminobutyric acid (Abu), Z has at least 85% identity to SEQ ID NO:1 and has the formula R2—R3—R4—R5—R6—R7—R8, R9 is selected from lysine (K), ornithine (Orn), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), or N-methyl lysine (NMe-K), and Y1 is absent or is a single amino acid extension or a two amino acid extension attached to R9.
The cyclic structure is defined such that R1 or R2 is connected to R9, and the disclosed examples include Ang(1-7) analogs such as TCAng04 (SEQ ID NO:5) and TCAng05 (SEQ ID NO:6), including L-TCAng05 (SEQ ID NO:7). The examples further include enumerated peptide series, and specific structural variants are described, including a lactam bridge connecting defined positions. The document frames the analogs within the Ang(1-7)/mas receptor axis, including receptor-mas-mediated action.
The problem being solved is presented as the need for Ang(1-7) (mas receptor) peptide analogs with improved properties for therapeutic use in cancer, including improved in vivo stability. The disclosed analogs are reported to show markedly longer plasma half-life for the analogs compared to native Ang-(1-7). The document associates the cyclic/lactam-bridged analog design with therapeutic performance, including in vitro growth inhibition and in vivo tumor growth reduction.
The disclosed therapeutic approach is directed to treating and/or preventing cancer by inhibiting mas activity using the peptide analogs, and the document reports evaluation markers consistent with reduced cell proliferation and reduced angiogenesis and fibrosis. The reported outcomes include reduction of Ki67 and reduction of CD34 angiogenesis markers, and reduction of Picrosirius red fibrosis/collagen markers, alongside tumor growth inhibition in vivo. The document further includes pharmaceutical compositions using pharmaceutically acceptable carriers and describes therapeutic administration for cancer-related outcomes.
Claims Coverage
The independent claim clm-00001 covers a peptide defined by a specific cyclic R1—Z—R9—Y1 scaffold (or SEQ ID NO:5) with R1 and R9 restricted to selected amino acids, Z constrained to at least 85% identity to SEQ ID NO:1, Y1 limited to absence or short extension, and a cyclic connectivity condition linking R1 or R2 to R9.
Cyclic R1—Z—R9—Y1 mas receptor peptide scaffold
A peptide comprising a compound of the formula R1—Z—R9—Y1, wherein R1 is selected from norleucine (Nle), leucine (L), alanine (A), norvaline (Nva), azidohomoalanine (Aha), or 2-Aminobutyric acid (Abu); Z has at least 85% identity to SEQ ID NO:1 and has the formula R2—R3—R4—R5—R6—R7—R8; R9 is selected from lysine (K), ornithine (Orn), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), or N-methyl lysine (NMe-K); and Y1 is absent or is a single amino acid extension or a two amino acid extension attached to R9.
Connectivity-defined cyclic structure linking R1 or R2 to R9
The peptide has a cyclic structure, wherein R1—Z—R9 has a cyclic structure with connectivity such that R1 or R2 is connected to R9; or the peptide comprises SEQ ID NO:5.
Overall, the claim coverage centers on a cyclic mas receptor peptide analog framework defined by restricted selections for R1 and R9, a Z segment constrained by identity to SEQ ID NO:1, limited Y1 extension, and a cyclic connectivity rule linking R1 or R2 to R9, with an alternative encompassed peptide sequence specified as SEQ ID NO:5.
Stated Advantages
Markedly longer plasma half-life for the peptide analogs compared to native Ang-(1-7).
In vitro growth inhibition using cancer cell lines including MDA-MB-231 and A549.
Receptor-mas-mediated action, including mas activity inhibition demonstrated with antagonist blockade using D-Ala7-Ang-(1-7).
In vivo tumor growth reduction, including dose-dependent effects with subcutaneous and oral dosing.
Reduction of mechanism markers associated with decreased proliferation (Ki67) and decreased angiogenesis (CD34) and decreased fibrosis/collagen (Picrosirius red).
Documented Applications
Treating and/or preventing cancer by administering the disclosed peptide analogs to inhibit mas activity.
Using the peptide analogs to inhibit mas activity in the context of cancer, with reported in vitro growth inhibition and in vivo tumor growth reduction.
In vivo evaluation in cancer models including a subcutaneous tumor growth context and an oral dosing context, with reported outcomes measured by Ki67, CD34, and Picrosirius red markers.
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