Discovery of novel peptide dendrimers with potent and broad spectrum of antimicrobial activity
ABSTRACT:Discovery of novel peptide dendrimers with potent and broad spectrum of antimicrobial activity
Thissa N. Siriwardena and Jean-Louis Reymond*
University of Bern
Multidrug resistant (MDR) Pseudomonas aeruginosa and Acinetobacter baumannii have been listed, together with Enterobacteriaceae, as the most critical human pathogens by the World Health More Organization in 2017. New antibiotics are urgently needed to address MDR bacteria. We recently reported antimicrobial peptide dendrimer (AMPD) G3KL, showing good activity against P. aeruginosa and other Gram-negative strains including MDR clinical isolates.1 We later optimized this dendrimer to a smaller lipidated analog, TNS18, which showed excellent activity against both gram negative and positive bacteria and was also active in a murine infection model against MDR clinical isolates of A. baumannii and E. coli.2 Here we report our latest progress in identifying new AMPD exploiting the concept of chemical space borrowed from small molecule cheminformatics and recently exemplified with bicyclic peptides.3 Our exploration of the dendrimer chemical space led us to the discovery of a more potent analogs of G3KL with an expanded activity range, improved serum stability and very good activity in an in vivo infection model.
1. Stach, M.; Siriwardena, T. N.; Kohler, T.; van Delden, C.; Darbre, T.; Reymond, J. L. Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug-Resistant Pseudomonas Aeruginosa. Angew. Chem., Int. Ed. 2014, 53, 12827-12831.
2. Siriwardena, T. N.; Stach, M.; He, R.; Gan, B. H.; Javor, S.; Heitz, M.; Ma, L.; Cai, X.; Chen, P.; Wei, D.; Li, H.; Ma, J.; Kohler, T.; van Delden, C.; Darbre, T.; Reymond, J. L. Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria. J. Am. Chem. Soc. 2018, 140, 423-432.
3. Di Bonaventura, I.; Jin, X.; Visini, R.; Probst, D.; Javor, S.; Gan, B.-H. ; Michaud, G.; Natalello, A.; Doglia, S. M.; Kohler, T.; van Delden, C. ; Stocker, A.; Darbre, T.; Reymond, J.-L.; Chem. Sci. 2017, 8, 6784-6798.
Poster ID# 2973
Brain Penetrating IgG Fusion Proteins: from Genetic Engineering to Clinical Trials in Lysosomal Storage Disorders
ABSTRACT:Protein therapeutics can be re-engineer as brain penetrating IgG-fusion proteins for the CNS treatment of rare disorders, like Lysosomal Storage Disorders (LSD). Lysosomal enzymes, such as iduronase (IDUA) and sulfatases, are large molecule drugs that do not cross the blood-brain barrier (BBB). The BBB-penetration of enzyme therapeutics is enabled More by re-engineering the recombinant enzyme as bi-functional IgG fusion proteins, wherein the IgG domain targets a specific endogenous receptor-mediated transporter system within the BBB, such as the human insulin receptor (HIR). The enzyme therapeutic domain of the fusion protein exerts the pharmacological effect in brain once across the BBB. Several brain penetrating IgG-fusion proteins have been engineered and validated. First in human proof of concept phase II clinical trial in LSD will be discussed.
Note that this is scheduled for oral presentation in the Scientific Session 2: Drug Delivery, Wednesday September 26, 2018, 9:30-12:30. Thanks