Selective poly-N-substituted glycine antibiotics
Inventors
Barron, Annelise E. • Czyzewski, Ann M. • Dohm, Michelle T. • Miller, Tyler M. • Zuckermann, Ronald N. • Patch, James A. • Chongsiriwatana, Nathaniel P.
Assignees
Ronald N Zuckermann • Maxwell Biosciences Inc
Publication Number
US-8445632-B2
Publication Date
2013-05-21
Expiration Date
2029-02-09
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Abstract
Antimicrobial peptoid compounds and related compositions as can be used against bacteria effectively and selectively.
Core Innovation
The invention provides a novel class of antimicrobial compounds based on poly-N-substituted glycine structures, known as peptoids. These compounds are designed to mimic the structure and function of natural antimicrobial peptides (AMPs) while overcoming key limitations associated with peptide therapeutics, such as rapid in vivo degradation and susceptibility to proteolysis. The peptoid structure enables sequence-specific design with side chains attached to the backbone amide nitrogen, allowing for facile synthesis and extensive chemical diversity.
This invention addresses the problem of existing AMPs having limited clinical utility due to their instability and high degradation in biological environments, which diminishes bioavailability. By creating peptoid-based AMP mimics that are protease-resistant, structurally versatile, and capable of adopting amphipathic helical conformations, the technology enables the development of potent and selective antibiotics that retain or improve upon the spectrum of activity possessed by natural AMPs.
Distinctive features include the ability to fine-tune activity and selectivity of peptoids through sequence and side-chain modification. Peptoids constructed according to the invention demonstrate low micromolar antibacterial activity against both Gram-positive and Gram-negative bacteria, with reduced cytotoxicity and negligible hemolysis in mammalian cells. Additionally, alkylation at the N-terminus allows for active compounds of shorter lengths, expanding the potential for lower molecular weight therapeutics that are both potent and selective.
Claims Coverage
The patent contains three independent claims, each directed to a specific class or structural variant of poly-N-substituted glycine antibiotic compounds.
Poly-N-substituted glycine antibiotic compounds of specified formula
Defines poly-N-substituted glycine compounds having the formula A-[X-Y-Z]_n-B, in which: - A is selected from H or a terminal N-alkyl substituted glycine (alkyl of about C4 to about C20, linear, branched, or cyclic). - n is an integer from 1–3. - B is selected from NH2, and one or two N-substituted glycine residues, with N-substituents that are α-amino acid side chain moieties or analogs. - X, Y, and Z are independently N-substituted glycine residues, N-substituents are α-amino acid side chain moieties and analogs (including proline). Features include: - The ability to tune hydrophobicity, amphipathicity, and selectivity by selecting residue sequence and/or N-substituent, as well as variable monomer numbers and lengths. - Embodiments where at least one of Y and Z (or both) are proline residues, and/or where compounds have reduced hydrophobicity relative to compounds of 3-fold periodicity. - Coverage for both H and N-alkyl substituted glycine N-termini and a range of C-termini and monomeric sequences.
Poly-N-alkyl substituted glycine antibiotic compounds with specified structural properties
Defines poly-N-alkyl substituted glycine compounds of the formula: R—X—[Y—Z]_n—B, in which: - R is an N-alkyl substituent (about C4 to about C20 linear, branched, or cyclic alkyl). - X, Y, Z, and X′ are independently N-substituted glycine residues, with N-substituents as α-amino acid side chain moieties and their carbon homologs. - n is an integer from 1–2. - B is NH2 or X′. Features include: - Embodiments where n is 2 and B is NH2, or where n is 1 and B is X′. - At least one of X and X′ may be NLys residues, and R may be a specified C6 to C18 alkyl. - Examples include specific compounds such as H—Ntridec—NLys—Nspe—Nspe—NLys—NH2.
Poly-N-substituted glycine compounds with N-alkyl substituted glycine N-terminus and non-periodic sequence
Defines poly-N-substituted glycine compounds comprising: - An N-terminus selected from H or N-alkyl substituted glycine residue (alkyl of about C4 to about C20). - A C-terminus selected from NH2, one or two N-substituted glycine residues (N-substituents as α-amino acid side chain moieties, isomers, or carbon homologs). - 2 to about 15 monomeric residues between the termini, independently selected from proline and N-substituted glycine residues (N-substituents as natural α-amino acid side chains, isomers, or carbon homologs). - At least one monomeric residue is NLys and at least one N-substituent is chiral. - The monomeric residues are selected to provide a non-periodic sequence. Embodiments include N-terminus as N-alkyl substituted glycine with alkyl of about C6 to about C18, 2–5 (X-Y-Z) non-periodic trimers, sequences where 3-fold periodicity is interrupted, and at least two non-consecutive repeat trimers separated by other residues.
The claims provide broad and detailed coverage for new classes and structural motifs of poly-N-substituted glycine antibiotic compounds, including their sequence, terminal modifications, and non-periodicity, which enables fine-tuning of antibiotic specificity and selectivity.
Stated Advantages
Provides compounds with minimum inhibitory concentrations in the low micromolar range against both Gram-positive and Gram-negative bacteria.
Demonstrates lower mammalian cytotoxicity and negligible hemolysis at active concentrations compared to prior art compounds.
Enables fine-tuning of antibacterial activity and selectivity through control of sequence, side chain, and hydrophobicity.
Allows creation of potent and selective antibiotic compounds at shorter chain lengths and lower molecular weights than previously possible.
Offers functional and structural analogy to natural antimicrobial peptides, reducing the likelihood of rapid bacterial resistance development.
Yields compounds that are protease-resistant and stable, providing improved bioavailability and stability over conventional peptides.
Permits efficient, low-cost, and diverse synthesis using established solid phase methods and primary amine submonomers.
Demonstrates efficacy in vivo in reducing bacterial counts in mammalian (mouse) infection models without inducing fatality.
Documented Applications
Use of poly-N-substituted glycine (peptoid) compounds and compositions as antibiotics for treatment of bacterial infections, including both in vitro and in vivo administration.
Formulation of pharmaceutical compositions comprising one or more of the described polypeptoid/ampetoid compounds with or without additional antimicrobial components and a pharmaceutically acceptable carrier.
Treatment of infections in a mammalian system, demonstrated via an intraperitoneal injection mouse model resulting in reduced bacterial counts.
Antifungal activity, demonstrated by potent and selective inhibition of Candida albicans growth.
Combination of inventive peptoids with antimicrobial peptides and/or peptidomimetic compounds known in the art for bacteria or microbial treatment.
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