Synthesis, and functional properties of a modified human insulin A-chain: implication in a 'mini-insulin' structure determination.
The design and total synthesis of a novel insulin A-chain mutant, analogue 3, is reported. In this compound, the cysteines implied in the two insulin inter-chain disulfide bridges are replaced by two serines (residues Ser(A7) and Ser(A20)) and the intra-A-chain disulfide bridge (residues Cys(A6) and Cys(A11)) is conserved. This A-chain analogue (3) has been tested in three in vitro cell culture assays, using insulin as a reference. The data clearly showed that analogue 3 mimics insulin effects on DNA synthesis, glucose uptake and glycogen synthesis without loss of potency as compared to insulin. To our knowledge, these are the first results showing that an isolated insulin chain displays functional properties similar to those of insulin. The implication of these new findings in insulin structure-function relationships and in a 'mini-insulin' structure determination is discussed.
Le Flem
Guillaume
G
GRPD, UPRES EA 2629, Faculté de Pharmacie et de Médecine, 1-3 rue des Louvels, 80037 Amiens Cedex 1, France.
Dupradeau
François-Yves
FY
Pujol
Jean-Pierre
JP
Monti
Jean-Pierre
JP
Bogdanowicz
Patrick
P
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D007328:Insulin; D006003:Glycogen; D005947:Glucose