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Publication Number
US-10351599-B2
Publication Date
2019-07-16
Expiration Date
Abstract
Described herein are anti-microbial peptides having enhanced activity and transport.
Core Innovation
The invention relates to a non-naturally occurring anti-microbial peptide comprising between 7 and 17 residues and having a sequence according to Formula I. The peptide includes optional N-terminal stabilizing residues X1 to X3, residues R1 to R17 under residue-identity constraints, and degradation-resistant C-terminal stabilizing residues Y1 to Y3.
In the peptide of Formula I, R1 and R2 are absent or arginine, R3 is aspartic acid, and at least one of R7 to R14 is lysine. The peptide is cyclized through a side chain lactam between R3 and said lysine, and Y1 to Y2 is selected from listed degradation-resistant D-/β-amino-acid dipeptides, with Y3 absent.
The specification describes rationally designed non-naturally occurring antimicrobial peptides with enhanced antimicrobial activity and transport, including N- and/or C-terminal degradation-resistant extensions, optional acylation/amidation, and cyclization including lactam linkage. It also describes hybrid constructs in which an anti-biofilm peptide is covalently linked to the AMP, optionally via linkers, to provide anti-biofilm and anti-microbial activity.
Claims Coverage
The consolidated claim coverage identifies one independent claim defining a Formula I non-naturally occurring anti-microbial peptide, with dependent claims refining optional N-terminal stabilizing residues, C-terminal amidation, and specific residue substitutions. The independent claim centers on lactam cyclization, residue-identity constraints, and degradation-resistant C-terminal stabilization, with one claim set also describing a specific Y1–Y2 segment of D-Val–D-Pro.
Formula I non-naturally occurring anti-microbial peptide
A non-naturally occurring anti-microbial peptide comprising between 7 and 17 residues with a sequence according to Formula I, including optional N-terminal stabilizing residues X1–X3, anti-microbial residues R1–R17 subject to defined identity constraints, and degradation-resistant C-terminal stabilizing residues Y1–Y3.
Side chain lactam cyclization between R3 and lysine
R3 is aspartic acid, at least one of R7 to R14 is lysine, and the peptide is cyclized through a side chain lactam between R3 and said lysine.
Degradation-resistant C-terminal stabilization with Y3 absent
Y1–Y2 is selected from listed degradation-resistant D-/β-amino-acid dipeptides, and Y3 is absent.
Restricted optional N-terminal stabilizing residues
X1, X2, and X3 are independently chosen and each is absent or selected from a specified set of D- and L-amino acids and a piperazin-2-one ring.
Amidated C-terminus and defined residue substitutions
Dependent claims describe an amidated C-terminus and specific residue substitutions at R4–R10, together with Y1–Y2 being D-Val–D-Pro.
The claims consistently focus on a Formula I non-naturally occurring antimicrobial peptide with residue-identity constraints, lactam cyclization between R3 and a lysine-containing position, and degradation-resistant C-terminal stabilization with Y3 absent. Dependent claims narrow the N-terminal stabilizing residues and add an amidated C-terminus and specific residue substitutions.
Stated Advantages
Enhanced antimicrobial activity and transport.
Overcoming proteolysis by using degradation-resistant N- and/or C-terminal extensions.
Oral activity and blood-brain-barrier transport via specified peptide extensions.
Selective targeting of gram-positive vs gram-negative bacteria.
Anti-biofilm activity, including selectivity/anti-biofilm activity in biofilm assays.
Improves weight gain while reducing infection when used as an animal-feed additive.
Improves feed conversion when used as an animal-feed additive.
Decreases acetate/methane and alters rumen fermentation while proportionally affecting growth parameters.
Reduced adhesion in biofilms for an anti-biofilm/anti-microbial peptide AB01.
Improved potency of AB01 versus controls.
Plasma stability is described in canine study context.
Documented Applications
Use in achieving oral activity (gastrointestinal transport) and blood-brain-barrier transport.
Antimicrobial and selective antibacterial activity against gram-positive vs gram-negative bacteria, including bacterial cell agglutination and MIC/IC50 outcomes.
Anti-biofilm activity using hybrid anti-biofilm/anti-microbial peptides, including biofilm assays and reduced adhesion in biofilms.
In vivo safety and plasma stability observations in canines for TCAM207 and related constructs.
Veterinary use as animal-feed additives using anti-microbial peptides to improve weight gain and feed conversion while reducing infection.
Animal production/rumen modulation use where anti-microbial peptides decrease acetate/methane and alter rumen fermentation and proportionally affect growth parameters.
Feed additive synergy with antibiotics, proposing co-use to reduce total antibiotic dose.
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