Feglymycin, a Novel Inhibitor of the Replication of the Human Immunodeficiency Virus. Fermentation, Isolation and Structure Elucidation.

Abstract

The novel peptide feglymycin has been isolated from cultures of Streptomyces sp. DSM 11171 by solid phase extraction, size exclusion chromatography and repeated reversed-phase chromatography. The molecular weight was found to be 1900.90 g/mol and the molecular formula is C95H97N13O30. Feglymycin contains 13 amino acids of which four are 3-hydroxyphenylglycine and five are 3,5-dihydroxyphenylglycine residues. The

Total Synthesis of the Antiviral Peptide Antibiotic Feglymycin

“…Synthetic 1 (and 1') exhibited identical physical properties (R f , HPLC, 1 H NMR, MS) to those of natural feglymycin. [1,18] For the investigation of biological activity, the natural product and a selection of synthetic intermediates were chosen for antiviral testing (see the Supporting Information for complete data). The anti-HIV-1 activity of the compounds was evaluated in the human MT-4 cell line.…”

“…DSM 11171, strongly inhibits the formation of HIV syncytia in vitro and was reported to show weak antibacterial activity against Gram-positive bacteria. [1] The molecular structure of 1 was first determined by mass spectrometry and NMR spectroscopy in the mid-1990s and was proven in 2005 by Sheldrick and co-workers by X-ray crystallography. [2] The unusual primary structure of 1 consists of an alternating sequence of mostly aromatic S-and Rconfigured amino acid residues.…”

“…However, the exposure of the C-terminally protected 13-mer to the same cleavage conditions resulted in almost complete decomposition of the substrate. Since the thermal cleavage of the Boc group also did not occur reproducibly (T > 100 8C), [14] a benzyloxycarbonyl (Cbz) group was introduced on (R)- 1 Hpg. This approach enabled simultaneous Nand C-terminal deprotection of three benzylic groups from the 13-mer peptide by hydrogenolysis under mild conditions.…”

Totalsynthese des antiviralen Peptidantibiotikums Feglymycin

“…Sowohl 1 als auch 1' wiesen identische physikalische Eigenschaften (R f , HPLC, 1 H-NMR, MS) wie natürliches Feglymycin auf. [1,18] Zur Untersuchung der biologischen Aktivität wurden einige synthetische Peptidintermediate zusammen mit dem Naturstoff für antiretrovirale Tests ausgewählt (kompletter Datensatz siehe Hintergrundinformationen). Die Anti-HIV-1-Aktivität dieser Verbindungen wurde in Zellkultur in menschlichen MT-4-Zellen ermittelt.…”

“…Zudem wurde eine schwach antibakterielle Aktivität gegen Grampositive Bakterien beschrieben. [1] Die Struktur von 1 wurde zunächst durch massenspektrometrische Methoden und NMR-Spektroskopie in der Mitte der 90er Jahre aufgeklärt und 2005 nach Lösung der Röntgenkristallstruktur durch Sheldrick et al bestätigt. [2] Die ungewöhnliche Primärsequenz von 1 besteht überwiegend aus einer alternierenden Sequenz aromatischer (S)-und (R)-konfigurierter Aminosäuren.…”