Engineering pro-angiogenic peptides using stable, disulfide-rich cyclic scaffolds

Fragments from the extracellular matrix proteins laminin and osteopontin and a sequence from VEGF have potent proangiogenic activity despite their small size (< 10 residues). However, these linear peptides have limited potential as drug candidates for therapeutic angiogenesis because of their poor stability. In the present study, we show that the therapeutic potential of these peptides can be significantly improved by "grafting" them into cyclic peptide scaffolds. Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) and sunflower trypsin inhibitor-1 (SFTI-1), naturally occurring, plant-derived cyclic peptides of 34 and 14 residues, respectively, were used as scaffolds in this study. Using this approach, we have designed a peptide that, in contrast to the small peptide fragments, is stable in human serum and at nanomolar concentration induces angiogenesis in vivo. This is the first report of using these scaffolds to improve the activity and stability of angiogenic peptide sequences and is a promising approach for promoting angiogenesis for therapeutic uses.     

Cyclotides: a patent review

INTRODUCTION: Cyclotides are bioactive mini-proteins from plants that have the unique topological feature of a head-to-tail cyclic backbone combined with a cystine knot. Because of this structure they are ultra-stable and have attracted interest as peptide-based templates for drug design applications. Cyclotide biosynthesis involves processing from a genetically encoded precursor protein but methods have been developed for their man-made synthesis using solid phase peptide synthesis as well as recombinant methods. Their natural function in plants is as insecticidal agents and thus they have potential applications in agriculture. However, they have a range of pharmaceutically relevant activities, including anti-HIV, antimicrobial and uterotonic activity. Their exceptional stability and facile synthesis lend them to uses as pharmaceutical templates into which bioactive peptide sequences can be grafted. AREAS COVERED: This article reviews the patent literature associated with cyclotides with a focus on therapeutic applications. These patents are primarily related to the use of cystine knot scaffolds for the production of peptide-based drug leads, molecular probes or diagnostic agents. EXPERT OPINION: Although no cyclotide-related peptide has yet reached clinical trials, proof-of-concept has been obtained that bioactive peptide sequences can be grafted onto a cyclotide framework, maintaining biological activity while becoming resistant to proteolysis. Thus, cyclotides are promising templates in drug development applications and there is increasing interest in them and related cystine knot scaffolds, as well as in the use of other disulfide-rich scaffolds, in drug design.     

Cyclotides as a basis for drug design

INTRODUCTION: Cyclotides are plant-made defence proteins with a head-to-tail cyclic backbone combined with a conserved, six cystine knot. They have a range of biological activities, including uterotonic and anti-HIV activity, which have attracted attention to their potential pharmaceutical applications. Furthermore, their unique structures and high stability make them appealing as peptide-based templates for drug design applications. Methods have been developed for their production, including solid phase peptide synthesis as well as recombinant methods. AREAS COVERED: This article reviews the recent literature associated with therapeutic applications of naturally occurring and synthetically modified cyclotides. It includes applications of cyclotides and cyclotide-like molecules as peptide-based drug leads and diagnostic agents. EXPERT OPINION: The ultra-stable cyclotides are promising templates for drug development applications and are currently being assessed for the potential breadth of their applications. For synthetic versions of cyclotides to enter human clinical trials further studies to examine their biopharmaceutical properties and toxicities are required. However, several promising proof-of-concept studies have established that pharmaceutically relevant bioactive peptide sequences can be grafted into cyclotide frameworks and thereby stabilised, while maintaining biological activity. These studies include examples directed at cancer, cardiovascular disease and infectious diseases. Solid phase peptide synthesis has been the preferred approach for making pharmaceutically modified cyclotides so far, but promising progress is being made in biological approaches to cyclotide production.     

The effects of attention switching on encoding and retrieval of words in younger and older adults

Two experiments examined the interaction between aging, attention switching, encoding process, and recognition memory using different versions of a cued attention switching paradigm. In Experiment 1, 30 younger and 35 older adults encoded words based on font color, meaning, or by explicit learning with a color response during performance of a choice-reaction time (RT) task. Attention switches were cued by means of stimulus location, and occurred on average every seven trials. In Experiment 2, attention switching was precued from a central fixation point and the number of critical switch trials was increased, occurring on average every four trials. Memory was assessed in both experiments by means of a forced-choice recognition task. Results indicated that, relative to color encoding, older adults benefited more than younger adults from semantic encoding, but less from explicit learning instructions. Attention switching disrupted encoding task performance of older adults more than that of younger adults, but recognition memory was generally unaffected. Results are discussed in light of theoretical models of aging memory that posit a role for executive control processing.