Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery.
Cyclotides are a unique and growing family of backbone cyclized peptides that also contain a cystine knot motif built from six conserved cysteine residues. This unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size. Aside from the conserved residues forming the cystine knot, cyclotides have been shown to have high variability in their sequences. Consisting of over 160 known members, cyclotides have many biological activities, ranging from anti-HIV, antimicrobial, hemolytic, and uterotonic capabilities; additionally, some cyclotides have been shown to have cell penetrating properties. Originally discovered and isolated from plants, cyclotides can also be produced synthetically and recombinantly. The high sequence variability, stability, and cell penetrating properties of cyclotides make them potential scaffolds to be used to graft known active peptides or engineer peptide-based drug design. The present review reports recent findings in the biological diversity and therapeutic potential of natural and engineered cyclotides.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
Andrew
A
Gould
Yanbin
Y
Ji
Teshome L
TL
Aboye
Julio A
JA
Camarero
D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D018360:Crystallography, X-Ray; D047169:Cyclotides / Q000138:chemical synthesis / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology; D047168:Cystine Knot Motifs / Q000235:genetics; D055808:Drug Discovery / Q000379:methods*; D004355:Drug Stability; D005818:Genetic Engineering; D006801:Humans; D008958:Models, Molecular; D019151:Peptide Library; D030821:Plants, Genetically Modified / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D055550:Protein Stability
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D047169:Cyclotides; D019151:Peptide Library