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Publication Number
US-10954271-B2
Publication Date
2021-03-23
Expiration Date
Abstract
Described herein are anti-microbial peptides having enhanced activity and transport.
Core Innovation
The invention is directed to a non-naturally occurring anti-microbial peptide specified by a sequence according to Formula I, comprising between 5 and 15 natural, synthetic, or chemically modified residues and a defined arrangement of residue positions X1 to X3, R1 to R17, and optional degradation-resistant C-terminal stabilizing residues Y1 to Y3. The peptide has R3 as aspartic acid and at least one of R7 to R14 as Lys.
A defining feature is cyclization through a side chain lactam between R3 and one of the at least one Lys. The sequence also includes an anti-biofilm peptide covalently linked to the N-terminus, where the anti-biofilm peptide has the specific sequence Phe-Arg-Ile-Arg-Val-Arg-Val.
The disclosed embodiments describe anti-biofilm linked variants and related peptide families with positional residue choices and C-terminal variants, including amidation (NH2) and specified C-terminal combinations such as D-Pro-D-Val-NH2, D-Pro-D-Phe-NH2, and D-Val-D-Phe-NH2. The broader content also describes orally active antimicrobial/anti-biofilm peptides, reported oral stability, selectivity between Gram-positive bacteria and Gram-negative bacteria, and lactam-ring conformational stabilization linked to transport across the blood brain barrier.
Claims Coverage
The independent claim coverage centers on one inventive feature set: a non-naturally occurring antimicrobial peptide genus defined by Formula I, cyclized through a side chain lactam, and covalently linked at the N-terminus to a specific anti-biofilm peptide sequence, with optional C-terminal stabilizing residues. Three inventive features are identified across the independent claim scope.
Formula I-defined non-naturally occurring antimicrobial peptide
A non-naturally occurring anti-microbial peptide comprising between 5 and 15 natural, synthetic, or chemically modified residues, the peptide comprising the sequence according to Formula I with X1, X2, X3 absent and with R1 and R2 absent, R3 as aspartic acid, defined sets for R4 to R14, and optional degradation-resistant C-terminal stabilizing residues Y1 to Y3.
Side-chain lactam cyclization between R3 and a lysine position
The antimicrobial peptide is cyclized through a side chain lactam between R3 and one of the at least one Lys, where at least one of R7 to R14 is Lys.
N-terminal covalent linkage to a specific anti-biofilm peptide sequence
An anti-biofilm peptide is covalently linked to the N-terminus of the antimicrobial peptide, the anti-biofilm peptide having the sequence Phe-Arg-Ile-Arg-Val-Arg-Val.
Across the independent-claim scope, the inventive elements combine a Formula I-defined non-naturally occurring antimicrobial peptide with specified absent/present residue constraints and optional C-terminal stabilizing residues, cyclization through a side chain lactam between an aspartic acid position (R3) and a Lys position within the defined region, and a covalent N-terminally linked anti-biofilm peptide moiety with the sequence Phe-Arg-Ile-Arg-Val-Arg-Val.
Stated Advantages
Enhanced antimicrobial activity and transport properties.
Support for oral activity and/or blood-brain barrier transport through degradation-resistant N- and/or C-terminal extensions.
Single-molecule anti-biofilm/anti-microbial activity via covalent linkage of the anti-biofilm peptide to the antimicrobial peptide.
Directed Gram-positive vs Gram-negative specificity via defined C-terminal dipeptides.
Oral activity is described, including oral stability up to 24 h.
Reported selectivity between Gram-positive bacteria and Gram-negative bacteria is described.
Lactam-ring conformational stabilization is described as relevant to oral blood brain barrier transport.
Anti-biofilm potency is described, including hybrid AB01 anti-biofilm potency and MIC values.
Canine safety and PK clearance is described.
Animal-feed use is described to improve weight gain and feed conversion and reduce infection and antibiotic resistance development.
Additional described performance effects in animal feed include reduced acetate and methane, altered propionate, and improved nitrogen and dry matter digestion.
Documented Applications
Therapeutic use context, including support for oral activity and blood-brain barrier transport.
Anti-biofilm/anti-microbial activity using an M. smegmatis adhesion/biofilm model.
Safety/PK observations for TCAM207 in a canine safety model.
Oral antimicrobial and anti-biofilm use is described, including orally active hybrid antimicrobial/anti-biofilm peptides and oral stability up to 24 h.
Blood brain barrier transport relevance is described for lactam-ring conformational stabilization.
Animal-feed embodiment: antimicrobial peptides as feedstock additives to improve weight gain and feed conversion and reduce infection and antibiotic resistance development, with described changes in acetate, methane, propionate, and nitrogen and dry matter digestion.
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