Patented Peptide Derivatives

The peptide pyrrhocoricin, when administered intravenously in vivo, can protect mice from systemic Escherichia coli challenge. To improve the efficacy and activity spectrum, as well as to avoid potential high dose toxicity, Chaperone developed novel pyrrhocoricin derivatives. The new analogs show improved protease resistance while maintaining the in vitro and in vivo efficacy over a broad concentration and dose range. CHP-105, lead drug candidate, kills beta-lactam, tetracycline- or aminoglycoside-resistant strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the submicromolar or low micromolar concentration range. CHP-105 also kills Staphylococcus saprophyticus, and some strains of Pseudomonas aeruginosa. Remarkably, no resistance could be generated in laboratory conditions against the lead peptide. In a murine Haemophilus influenzae lung infection model, a single dose of the lead pyrrhocoricin analog significantly reduces the bacteria in the bronchoalveolar lavage when delivered intranasally. Chaperone implemented a thorough design process that started with the development of the optimal conditions for efficacy screening of pyrrhocoricin-based antibacterial peptides, continued with the assessment of the activity against resistant bacterial strains and clinical isolates and ended by demonstrating potential activity against acute systemic and local (lung and urinary tract) infection models in vivo. Beyond the imminent applicability of the lead peptide analogs for drug development, our design strategy can serve as a proof for the suitability of synthetic peptides as drug leads, even with a non-injectable administration route, provided the experimental conditions for efficacy screening and the drug design process are modified to suit synthetic peptides.

Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa are the three principal causes of Gram-negative bacterial pneumonia. Another common cause of pneumonia in children younger than 5 years and in adults older than 60 years is Haemophilus influenzae. Escherichia coli accounts for 50-85% of all urinary tract infections and Klebsiella pneumoniae is responsible for another 8-13%. The activity figures of the pyrrhocoricin analogs against Escherichia coli and Klebsiella pneumoniae are very promising as a number of patient populations are at risk for urinary tract infections, including newborns, particularly the premature, prepubertal girls, young boys, sexually active young women, elderly males, as well as 10% of woman over the age of 60 years. Indeed, antibiotic-resistant Klebsiella pneumoniae strains represent one of the biggest problems in recurrent urinary tract and respiratory tract infections, particularly for the elderly. Moreover, the ability of the pyrrhocoricins to kill resistant Salmonella strains indicates the potential utility of these peptides to treat gastrointestinal infections in the clinical setting. Salmonella typhimurium outbreaks are frequent events from North America to Australia, often exhibiting drug-resistant or multidrug-resistant properties.