peptidomimetic; synthetic vaccine; peptide; antibiotic; chemical biology
Andolina Gloria, Bencze László-Csaba, Zerbe Katja, Müller Maik, Steinmann Jessica, Kocherla Harsha, Mondal Milon, Sobek Jens, Moehle Kerstin, Malojčić Goran, Wollscheid Bernd, Robinson John A. (2018), A Peptidomimetic Antibiotic Interacts with the Periplasmic Domain of LptD from Pseudomonas aeruginosa, in ACS Chemical Biology
, 13(3), 666-675.
Zerbe Katja, Moehle Kerstin, Robinson John A. (2017), Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines, in Accounts of Chemical Research
, 50(6), 1323-1331.
Urfer Matthias (2016), A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli, in J. Biol. Chem.
, 291(4), 1921-1932.
Moehle K. (2016), Solution Structure and Dynamics of LptE from Pseudomonas aeruginosa, in Biochemistry
, 55(21), 2936-2943.
vanderMeijden (2015), Synthesis of a polymyxin derivative for photolabeling studies in the gram-negative bacterium Escherichia coli, in J. Pept. Sci.
, 21(3), 231-235.
Robinson John (2014), Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors, in Pure Appl. Chem.
, 86(10), 1483-1538.
Mann A. (2013), Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors, in J. Virology
, 87(10), 5868-5881.
Schmidt J. (2013), Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp, in Bioorg. Med. Chem.
, 21(18), 5806-5810.
Vetterli Stefan, Moehle Kerstin, Robinson John A., Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic ß-hairpin peptidomimetic antibiotics containing N-methylated amino acids, in Bioorganic and Medicinal Chemistry
, 24(24), 6332-6339.
The main field of this research involves the design, synthesis and biological activities of novel protein epitope mimetics. Protein epitope mimetics are synthetic molecules designed to mimic the surface epitopes of naturally occurring peptides and proteins that are important for biological activity. The epitopes of most interest here adopt ß-hairpin conformations. Mimetic design involves transplanting the hairpin epitope from the protein target of interest, and attaching this to an organic template. The mimetics then typically comprise cyclic peptides that adopt folded hairpin structures in solution. Using this design strategy we could show in previous work how it was possible to design new molecules with many different types of biological activity. In this project, we plan to continue these studies. We plan to investigate peptidomimetics that possess potent antimicrobial activity against Gram-negative bacteria, and against Pseudomonas spp. in particular. In earlier work we discovered a new family of peptidomimetics, with an unprecedented mechanism of antimicrobial action, involving inhibition of lipopolysaccharide transport by the outer membrane protein LptD. We propose to continue studies on these molecules and investigate how they interact with their target. We also plan to synthesize new derivatives with antibacterial activity against other important Gram-negative pathogens, and study their mechanisms of action. An important goal of this work is to develop new antibiotics that address the growing problem of drug resistance amongst bacteria, both in hospitals and the wider community. Another related area of interest is the study of protein epitopes implicated in mediating immune protection. We plan to synthesize new mimetics of epitopes that have been reported to mediate protection against infection by HIV-1. This work should aid the development of new synthetic vaccines that help to address the global health problem posed by HIV-1.