Postdoctoral Associate, Broad Institute of MIT and Harvard
Use of high throughput technologies to remove bottlenecks in drug design
Currently, major limitations exist to oral delivery of peptide based drugs, due to decreased stability in the digestive tract. We are generating libraries of stable therapeutics by using protein engineering within stable frameworks to tackle this problem. We have generated several promising candidates for orally available drugs for diabetes.
Abstract: Haiou Qu, Bronwyn J. Smithies, Thomas Durek, David J. Craik Cyclotides are a group of cysteine-rich peptides derived from plants. Their exceptional stability based on their head-to-tail cyclized backbone and cystine knot, together with their tolerance to sequence modifications, make them promising drug design scaffolds into which novel bioactive sequences may be grafted. These grafting applications are achievable by solid-phase peptide synthesis. This article describes recent developments in the chemical synthesis and enzyme-mediated cyclization of cyclotides.
Pub.: 24 Nov '16, Pinned: 29 Jun '17
Abstract: Cyclotides are ultra-stable peptides derived from plants. They are around 30 amino acids in size and are characterized by their head-to-tail cyclic backbone and cystine knot. Their exceptional stability and tolerance to sequence substitutions has led to their use as frameworks in drug design. This article describes recent developments in this field, particularly developments over the last two years relating to the grafting of bioactive peptide sequences into the cyclic cystine knot framework of cyclotides to stabilize the sequences. Grafted cyclotides have now been developed that interact with protein or enzyme targets, both extracellular and intracellular, as well as with cell surface receptors and membranes.
Pub.: 02 Mar '17, Pinned: 29 Jun '17
Abstract: Cyclotides are a large family of naturally occurring plant-derived macrocyclic cystine-knot peptides, with more than 400 having been identified in species from the Violaceae, Rubiaceae, Cucurbitaceae, Fabaceae, and Solanaceae families. Nevertheless, their specialized distribution within the plant kingdom remains poorly understood. In this study, the diversity of cyclotides was explored through the screening of 197 plants belonging to 43 different families. In total, 28 cyclotides were sequenced from 15 plant species, one of which belonged to the Rubiaceae and 14 to the Violaceae. Every Violaceae species screened contained cyclotides, but they were only sparsely represented in Rubiaceae and nonexistent in other families. The study thus supports the hypothesis that cyclotides are ubiquitous in the Violaceae, and it adds to the list of plants found to express kalata S and cycloviolacin O12. Finally, previous studies suggested the existence of cyclotide isoforms with either an Asn or an Asp at the C-terminal processing site of the cyclotide domain within the precursor proteins. Here we found that despite the discovery of a few cyclotides genuinely containing an Asp in loop 6 as evidenced by gene sequencing, deamidation of Asn during enzymatic digestion resulted in the artifactual presence of Asp isoforms. This result is consistent with studies suggesting that peptides can undergo deamidation after being subjected to external factors, including pH, temperature, and enzymatic digestion.
Pub.: 05 May '17, Pinned: 29 Jun '17
Abstract: A simple MD-based protocol is presented to accurately predict both the sequence and order of disulfide bond formation in proteins containing multiple cysteine residues. It provides a detailed description of their dynamical and structural features, which can be used to perform ensemble-averaged ECD calculations. Plant cyclotides are used as model compounds.
Pub.: 17 May '17, Pinned: 29 Jun '17
Abstract: Cyclotides are globular microproteins with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to chemical, thermal, and biological degradation compared to other peptides of similar size. In addition, cyclotides have been shown to be highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot. Cyclotides can also cross cellular membranes and are able to modulate intracellular protein-protein interactions, both in vitro and in vivo. All of these features make cyclotides highly promising as leads or frameworks for the design of peptide-based diagnostic and therapeutic tools. This article provides an overview on cyclotides and their applications as molecular imaging agents and peptide-based therapeutics.
Pub.: 26 May '17, Pinned: 29 Jun '17
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