{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T12:17:23Z","timestamp":1761394643780},"reference-count":31,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[1994,10,1]],"date-time":"1994-10-01T00:00:00Z","timestamp":780969600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"},{"start":{"date-parts":[[1994,10,1]],"date-time":"1994-10-01T00:00:00Z","timestamp":780969600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antivir Chem Chemother"],"published-print":{"date-parts":[[1994,10]]},"abstract":"<jats:p> From fermentations of Tolypocladium niveum supplemented with D-threonine, a novel natural cyclosporin, [Melle<jats:sup>4<\/jats:sup>]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<jats:sup>4<\/jats:sup>]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<jats:sup>4<\/jats:sup>]cyclosporin is discussed. In vitro biosynthesis of [Melle<jats:sup>4<\/jats:sup>]cyclosporin was achieved using the previously described enzymatic system [Lawen and Traber (1993) J Biol Chem268: 20452\u201320465], thereby demonstrating the high affinity of cyclosporin synthetase for isoleucine in position 4. <\/jats:p><jats:p> In a long series of cyclosporins obtained by in vitro and in vivo biosynthesis, [Melle<jats:sup>4<\/jats:sup>]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. <\/jats:p>","DOI":"10.1177\/095632029400500507","type":"journal-article","created":{"date-parts":[[2015,5,8]],"date-time":"2015-05-08T22:10:56Z","timestamp":1431123056000},"page":"331-339","update-policy":"http:\/\/dx.doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":41,"title":["[Melle<sup>4<\/sup>]Cyclosporin, a Novel Natural Cyclosporin with anti-HIV Activity: Structural Elucidation, Biosynthesis and Biological Properties"],"prefix":"10.1177","volume":"5","author":[{"given":"R.","family":"Traber","sequence":"first","affiliation":[{"name":"SANDOZ Pharma Ltd, Preclinical Research, CH-4002 Basel, Switzerland"}]},{"given":"H.","family":"Kobel","sequence":"additional","affiliation":[{"name":"SANDOZ Pharma Ltd, Preclinical Research, CH-4002 Basel, Switzerland"}]},{"given":"H.-R.","family":"Loosli","sequence":"additional","affiliation":[{"name":"SANDOZ Pharma Ltd, Preclinical Research, CH-4002 Basel, Switzerland"}]},{"given":"H.","family":"Senn","sequence":"additional","affiliation":[{"name":"SANDOZ Pharma Ltd, Preclinical Research, CH-4002 Basel, Switzerland"}]},{"given":"B.","family":"Rosenwirth","sequence":"additional","affiliation":[{"name":"SANDOZ Forschungsinstitut GmbH, A-1235 Vienna, Austria"}]},{"given":"A.","family":"Lawen","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biochemie und Molekulare Biologie, Technische Universit\u00e4t Berlin, Franklinstrasse 29, D-10587 Berlin, Germany and Max-Planck-Gesellschaft zur F\u00f6rderung der Wissenschaften, AG \u2018Enzymologie der Peptidbindung\u2019, Weinbergweg 16a, D-06120 Halle, Germany"}]}],"member":"179","published-online":{"date-parts":[[1994,10,1]]},"reference":[{"key":"bibr1-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(88)90071-2"},{"key":"bibr2-095632029400500507","first-page":"4","volume":"24","author":"Baumann G.","year":"1992","journal-title":"Transplant Proc"},{"key":"bibr3-095632029400500507","first-page":"9","volume":"38","author":"Borel J.F.","year":"1986","journal-title":"Prog Allergy"},{"key":"bibr4-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1980.tb06000.x"},{"key":"bibr5-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)50706-7"},{"key":"bibr6-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1007\/BF00928431"},{"key":"bibr7-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1016\/0141-0229(82)90110-7"},{"key":"bibr8-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1038\/337476a0"},{"key":"bibr9-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1126\/science.6238408"},{"key":"bibr10-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)38137-1"},{"volume-title":"Cyclosporin: Biological Activity and Clinical Application.","year":"1984","author":"Kahan R.D.","key":"bibr11-095632029400500507"},{"key":"bibr12-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.17.8351"},{"key":"bibr13-095632029400500507","doi-asserted-by":"publisher","DOI":"10.1007\/BF00498470"},{"key":"bibr14-095632029400500507","doi-asserted-by":"crossref","unstructured":"Komatsubara S., Kisumi M., Chibata I., Gregorio M.M.V., M\u00fcller U.S., and Crout D.H.G. (1977) Stereochemistry of the Conversions in vivo of L- and D-Threonine into 2-Oxobutanoic Acid by the L- and D-Threonine Dehydratases of Serratia marcescens. 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(1994) Inhibition of HIV-1 Replication by SDZ NIM 811, a Non-Immunosuppressive Cyclosporin A Analog. 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