Cyclosporins--new analogues by precursor directed biosynthesis

Area of Science:

• Biochemistry
• Immunology
• Mycology

Background:

• Cyclosporin A (ciclosporin) is a vital immunosuppressive drug derived from Tolypocladium inflatum.
• It belongs to a class of cyclic undecapeptides with significant clinical applications.

Purpose of the Study:

• To investigate the synthesis of novel cyclosporin analogues through targeted amino acid substitutions.
• To evaluate the immunosuppressive potential of these modified cyclosporins.

Main Methods:

• Utilized feeding experiments with specific precursor molecules like DL-alpha-allylglycine and L-beta-cyclohexylalanine.
• Introduced D-serine to substitute D-alanine at position 8.
• Produced and characterized various cyclosporin analogues, including [Allylgly2]cyclosporin A and [MeCyclohexylala1]cyclosporin A.

Main Results:

• Achieved specific incorporation of DL-alpha-allylglycine at position 2, yielding [Allylgly2]cyclosporin A.
• Demonstrated exclusive production of [MeCyclohexylala1]cyclosporin A by using L-beta-cyclohexylalanine.
• Confirmed successful substitution of D-alanine at position 8 with D-serine.

Conclusions:

• The synthesis of novel cyclosporin analogues through precursor feeding and amino acid substitution is feasible.
• The newly synthesized analogues, specifically [D-Ser8]cyclosporins and [Allylgly2]cyclosporin A, retain significant immunosuppressive activity.