Derivatisable Cyanobactin Analogues: A Semisynthetic Approach.
Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine-tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger-scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics.
Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Emilia
E
Oueis
Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Catherine
C
Adamson
Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Greg
G
Mann
Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
Hannes
H
Ludewig
John King Medicinal Chemistry Laboratory, School of Pharmacy, Queen's University, 97 Lisburn Road, Belfast, BT9 7BL, UK.
Philip
P
Redpath
John King Medicinal Chemistry Laboratory, School of Pharmacy, Queen's University, 97 Lisburn Road, Belfast, BT9 7BL, UK.
Marie
M
Migaud
Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK. njw3@st-and.ac.uk.
Nicholas J
NJ
Westwood
Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK. naismith@st-and.ac.uk.|State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China. naismith@st-and.ac.uk.
James H
JH
Naismith
D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D000595:Amino Acid Sequence; D002232:Carbocyanines / Q000737:chemistry; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D061565:Cycloaddition Reaction; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism*
D002232:Carbocyanines; D010456:Peptides, Cyclic; C085321:cyanine dye 5; D003300:Copper; C015102:dehydroalanine; D000409:Alanine
click chemistry; cyclic peptides; enzymatic reactions; macrocyclisation; patellamides