Cyclotides, a promising molecular scaffold for peptide-based therapeutics.
Cyclotides are a new emerging family of large plant-derived backbone-cyclized polypeptides (approximately 30 amino acids long) that share a disulfide-stabilized core (three disulfide bonds) characterized by an unusual knotted structure. Their unique circular backbone topology and knotted arrangement of three disulfide bonds make them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size. Currently, more than 100 sequences of different cyclotides have been characterized, and the number is expected to increase dramatically in the coming years. Considering their stability and biological activities like anti-HIV, uterotonic, and insecticidal, and also their abilities to cross the cell membrane, cyclotides can be exploited to develop new stable peptide-based drugs. We have recently demonstrated the intriguing possibility of producing libraries of cyclotides inside living bacterial cells. This opens the possibility to generate large genetically encoded libraries of cyclotides that can then be screened inside the cell for selecting particular biological activities in a high-throughput fashion. The present minireview reports the efforts carried out toward the selection of cyclotide-based compounds with specific biological activities for drug design.
Jagadish
Krishnappa
K
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
Camarero
Julio A
JA
D000595:Amino Acid Sequence; D047169:Cyclotides / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use*; D015195:Drug Design; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010940:Plant Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use*; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014357:Trypsin / Q000737:chemistry
D047169:Cyclotides; D019151:Peptide Library; D010940:Plant Proteins; D014357:Trypsin