08.15.2015
Winner of 2015 FAOBMB Award for Research Excellence: Professor David Craik (Australia)
Professor David Craik
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
Professor David Craik is one of Australia’s most renowned biological chemists, whose career is noteworthy for ground-breaking discoveries in the field of circular proteins and their applications in drug design and discovery. He has published more than 500 papers or book chapters and trained more than 60 PhD students. His career is distinguished by significant discoveries in the fields of peptide chemistry, NMR, drug design, structural biology, toxins, and biological chemistry, but arguably most influential is his seminal work on circular proteins.
Conventional proteins are biosynthesized on the ribosome as topologically linear chains of amino acids. These linear chains typically fold into complex three-dimensional shapes dictated by the amino acid sequence of the protein and these shapes largely determine a protein’s function. Professor Craik has shown that there are classes of naturally occurring proteins that have a critical post-translational modification, namely, a peptide bond that links their termini to form a circle. This modification engenders circular proteins with exceptional stability to heat, enzyme digestion, or harsh chemical treatments. Professor Craik’s discoveries have exciting applications in a wide range of fields, from drug design to agriculture, where stabilizing bioactive proteins is important.
His major contributions include: (i) the discovery of cyclotides, the largest known family of circular proteins; (ii) the first structural and functional characterizations of prototypic circular proteins in higher organisms; and (iii) the development of synthetically cyclized peptide toxins as drug leads. Essentially, he has made discoveries of new classes of proteins, generated new knowledge on their structure and function, and used this information to design and chemically re-engineer new classes of drug leads and agricultural pest control agents.
Professor Craik is acknowledged internationally as the founder of the cyclotide field and he has made major discoveries relating to their distribution, chemistry, biosynthesis, mode-of-action and applications in drug design and agriculture. He was one of the first to recognize that other families of ribosomally synthesized cyclic peptides exist. As examples from bacteria and animals emerged, Professor Craik was at the forefront of their structural characterization, reporting the first structures of q-defensins from animals and the threaded lasso peptide microcin J25 from bacteria, as well as new examples of cyclic peptides from plants.
The fundamental studies that Professor Craik undertook for the discovery of cyclotides and other families of circular proteins led him to postulate that it would be possible to chemically re-engineer conventional proteins to join their ends together and thereby confer on them the advantages of circular proteins. He demonstrated this particularly in the conotoxin field. Conotoxins are disulfide-rich peptides from the venoms of marine cone snails, predatory marine molluscs that live in tropical waters along the Australian coastline. Cone snails use these conotoxins for the immobilization of their prey but these toxins have attracted the attention of drug designers because of their potent activity against pharmaceutically relevant receptors in humans, including those associated with the transmission of pain signals in the nervous system. However, like most peptides, natural conotoxins are not orally active and are subject to proteolytic breakdown, thus limiting their potential as drugs (patients prefer ingesting rather than injecting drugs). Professor Craik showed that disulfide-rich peptides such as conotoxins could be artificially cyclised and thereby stabilised. Applying the methodology to re-engineer the conotoxin Vc1.1, his laboratory produced an orally active peptide-based drug lead 100-fold more potent than gabapentin, the leading clinically used drug for neuropathic pain.
In summary, Professor Craik is a leading international scientist in the field of circular ribosomally synthesized proteins. He published the first review on the topic in 2002 and was invited by the editors of Science to write a “Perspectives” of the field in 2006. He organized the 1st and 2nd International Conferences on Circular Proteins in 2009 and 2012, with the 3rd International Conference on Circular Proteins to be held in October 2015 (http://www.circularproteins.org).
