Beta-hairpin peptidomimetics

Inventors

Obrecht, Daniel • Luther, Anatol • Bernardini, Francesca • Zbinden, Peter

Assignees

Spexis AG

Abstract

Beta-hairpin peptidomimetics of the general formula (I), cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-T1-T2], and pharmaceutically acceptable salts thereof, with P1 to P12, T1 and T2 being elements as defined in the description and the claims, have Gram-negative antimicrobial activity to e.g. inhibit the growth or to kill microorganisms such as Klebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichia coli. They can be used as medicaments to treat or prevent infections or as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials.These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

Core Innovation

The invention relates to backbone-cyclic cationic peptide mimetics defined by general formula (I) as cyclo[P1-P12-T1-T2], in which the single elements T or P are connected in either direction from the carbonyl (C=O) point of attachment to the nitrogen (N) of the next element. The scaffold is constrained by specific allowable residues at T1, T2, and at P1 through P12, including pharmaceutically acceptable salts, and the document further enumerates preferred cyclo β-hairpin peptidomimetic sequence variants and salts.

The invention’s rationale is to stabilize a β-hairpin conformation by a loop-transplant/template strategy, yielding β-hairpin peptidomimetics as backbone-cyclic cationic peptide mimetics. The scaffold is designed to provide Gram-negative antimicrobial activity, including inhibition and/or killing of Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli, while maintaining the cyclized framework defined by formula (I).

The described functional outcomes include improved efficacy for treating infections related to Gram-negative bacteria, together with reduced hemolysis and reduced/no cytotoxicity. The document states therapeutic and preventive use contexts for medicaments, and it also includes use as disinfectants/preservatives for foodstuffs, cosmetics, medicaments, and nutrient materials against Gram-negative bacteria.

Claims Coverage

The independent claims cover a cyclized general-formula compound (I) for two main inventive application modes: treatment or prevention of Gram-negative bacterial infections and associated diseases, including therapeutic administration and medicament manufacture; and disinfecting or preserving nutrient-containing materials against Gram-negative bacteria, including disinfectant/preservative manufacture. Across the independent claims, the compound scope is the same cyclo[P1-P12-T1-T2] structure with enumerated residue options and a stated proviso linking allowable substitutions, while the method steps differ by medical treatment versus preservation/disinfection context.

Across the independent claims, the inventive coverage centers on administering or formulating backbone-cyclic cationic β-hairpin peptidomimetics of general formula (I), cyclo[P1-P12-T1-T2], with T/P connectivity and enumerated residues at T1, T2, and P1-P12 governed by the stated proviso linking substitution allowances. The claim set then applies this defined compound scaffold to specific method contexts: treatment/prevention of Gram-negative bacterial infections and associated diseases, including medicament manufacture and administration with physiologically acceptable or pharmaceutically inert carriers, and disinfection/preservation of nutrient-containing materials, including disinfectant/preservative manufacture and addition of a compound or composition with pharmaceutically inert carriers.

Stated Advantages

Documented Applications