Open Access[Melle4]Cyclosporin, a Novel Natural Cyclosporin with anti-HIV Activity: Structural Elucidation, Biosynthesis and Biological Properties
Author(s) -
René Traber,
H. Kobel,
HansRudolf Loosli,
Hans Senn,
Brigitte Rosenwirth,
Alfons Lawen
Publication year - 1994
Publication title -
antiviral chemistry and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.919
H-Index - 51
eISSN - 2040-2066
pISSN - 0956-3202
DOI - 10.1177/095632029400500507
Subject(s) - biosynthesis , biochemistry , biology , isoleucine , threonine , in vivo , stereochemistry , amino acid , in vitro , leucine , chemistry , enzyme , serine , genetics
From fermentations of Tolypocladium niveum supplemented with D-threonine, a novel natural cyclosporin, [Melle 4 ]cyclosporin, was isolated. Its structural elucidation is based on amino acid analysis and spectroscopic data; the amino acid sequence was deduced from two-dimensional NMR investigations applied to the iso-derivative of [Melle 4 ]cyclosporin which, in contrast to the natural product, is present as one homogenous conformation in solution. We show that one of the four N-methyl-L-leucine units of cyclosporin A, namely that in position 4, is replaced by N-methyl-L-isoleucine. The putative mechanism by which D-threonine induces in vivo biosynthesis of [Melle 4 ]cyclosporin is discussed. In vitro biosynthesis of [Melle 4 ]cyclosporin was achieved using the previously described enzymatic system [Lawen and Traber (1993) J Biol Chem268: 20452–20465], thereby demonstrating the high affinity of cyclosporin synthetase for isoleucine in position 4. In a long series of cyclosporins obtained by in vitro and in vivo biosynthesis, [Melle 4 ]cyclosporin represents the first example that is devoid of immunosuppressive efficacy while retaining strong binding to cyclophilin. It exerts potent in vitro anti-HIV-1 activity.