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Publication Number
US-8754042-B2
Publication Date
2014-06-17
Expiration Date
Abstract
The present invention relates to novel agents, pharmaceutical compositions containing them, and their use in therapy, particularly anti-microbial and anti-cancer therapy. In particular, the present invention relates to novel peptide-based compounds based on SEQ ID NO:40 which have surprisingly been shown to have inhibitory effects on the growth and/or viability of cells, particularly bacterial and cancer cells. Also provided are therapeutic and non-therapeutic methods which comprise the use of peptides of the invention.
Core Innovation
The invention concerns an oligopeptidic compound defined by the amino acid sequence YGRKKRRQRRRGKTLRVAKAIYKRYIE (SEQ ID NO: 40), or an amino acid sequence having at least 95% sequence identity to that sequence. Related forms and variants are described, including reverse and inverso forms, and a TAT-derived cell penetrating sequence concept is used for intracellular delivery.
The disclosed compounds are used to inhibit the growth and/or viability of bacterial cells and/or cancer cells selected from brain cancer cells, breast cancer cells, melanoma cells, neuroblastoma cells, and sarcoma cells. The document reports anti-cancer and anti-microbial activity for selected peptide constructs, including cytotoxic and cytostatic effects and effects associated with apoptosis in cancer cells.
Pharmaceutical compositions are described that include the oligopeptidic compound together with a pharmaceutically acceptable excipient, and kits are described that include the compound or the pharmaceutical composition together with a second therapeutically active agent from defined therapeutic classes. The document also supports biologic delivery and formulation concepts using CPP/protein transduction domain-based constructs and describes nucleic acid molecules encoding the peptide, including vectors and host cells.
Claims Coverage
The document provides two independent claims. Across these independent claims, the coverage centers on the SEQ ID NO: 40 oligopeptidic sequence and sequence-identity variants, together with activity against specified bacterial cells and cancer cell types, and claim refinements expand to stereochemistry, formulation, and kit combination contexts.
Oligopeptidic sequence-defined compound with growth and/or viability inhibition
An oligopeptidic compound comprising the amino acid sequence YGRKKRRQRRRGKTLRVAKAIYKRYIE (SEQ ID NO: 40), or an amino acid sequence having at least 95% sequence identity to the sequence of SEQ ID NO: 40, wherein the compound has activity in inhibiting the growth and/or viability of bacterial cells and/or cancer cells selected from the group consisting of brain cancer cells, breast cancer cells, melanoma cells, neuroblastoma cells, and sarcoma cells.
Oligopeptidic compound consisting of SEQ ID NO: 40
An oligopeptidic compound comprising the amino acid sequence YGRKKRRQRRRGKTLRVAKAIYKRYIE (SEQ ID NO: 40).
Overall, the claim set covers the SEQ ID NO: 40 oligopeptidic compound itself and close sequence-identity variants, where the compound exhibits activity inhibiting the growth and/or viability of specified cancer cell types and bacterial cells. Dependent claim coverage further specifies optional D-amino acid inclusion and expands to pharmaceutical compositions with an excipient and kit formats with a second therapeutically active agent from listed classes.
Stated Advantages
Inhibits the growth and/or viability of bacterial cells.
Inhibits the growth and/or viability of cancer cells selected from brain cancer cells, breast cancer cells, melanoma cells, neuroblastoma cells, and sarcoma cells.
Provides cytotoxic and cytostatic activity in cancer cells, including effects associated with apoptosis.
Provides cytotoxicity-associated membrane disruption/lysis effects.
Supports anti-tumour activity and improved survival in the described mouse 4T1 model.
Supports anti-microbial activity as described in the document.
Documented Applications
Anti-cancer/anti-tumour activity, including activity against brain cancer cells, breast cancer cells, melanoma cells, neuroblastoma cells, and sarcoma cells; supported by an anti-tumour mouse 4T1 model and improved survival.
Anti-microbial activity against bacterial cells, including growth and/or viability inhibition of selected bacteria described in the disclosure, with particular reference to MDROs and examples such as MRSA, escherichia coli, Staphylococcus aureus, Enterococcus, and Pseudomonas aeruginosa.
Anti-fungal activity is described, with reference to Candida albicans.
Pharmaceutical compositions comprising the oligopeptidic compound and a pharmaceutically acceptable excipient.
Kits including the oligopeptidic compound or its pharmaceutical composition together with a second therapeutically active agent selected from chemotherapy, anti-neoplastic, antibiotic, antiviral, or antifungal agent classes.
Intracellular delivery concept using HIV-TAT-based cell penetrating sequences/CPP/protein transduction domain constructs, including embodiments using nucleic acid encoding, vectors, and host cells as described.
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