In a systematic search for microbial products active in the syncytia inhibition assay (SIA)1}, two streptomycetes strains AA6532 (ATCC 55290) and AA3891 (ATCC 55286) were found to produce new antiviral antibiotics, named siamycins I and II, respectively. They are peptide group antibiotics structurally related to each other, and both show good inhibitory activity against HIV and HSV viruses. This paper describes the fermentation, isolation, physico-chemical properties and biological activities of siamycins I and II. Streptomyces sp. AA3891and AA6532were isolated from soil samples collected in Madhya Pradesh, India and Tokyo, Japan, respectively. Siamycin I was produced by the strain AA6532 in 500-ml Erlenmeyer flasks using medium composed of lactose 2%, dextrin (Nichiden Kagaku Co.) 2%, glucose 0.5%, corn steep liquor (Oji Corn Starch Co.) 1%, rice bran 1.5%, K2HPO4 0.05% and CoCl2-6H2O 0.0002%, pH 7.0. The flasks were shaken on a rotary shaker (200 rpm) at 28°C for 88 hours. Antibiotic production in the fermentation broth was estimated by the SIA. The medium for siamycin II herpes simplex viruses to antiviral agents. Antiviral Research 3: 223-234, 1986
The 21-amino acid peptides siamycin II (BMY-29303) and siamycin I (BMY-29304), derived from Streptomyces strains AA3891 and AA6532, respectively, have been found to inhibit HIV-1 fusion and viral replication in cell culture. The primary sequence of siamycin II is CLGIGSCNDFAGCGYAIVCFW. Siamycin I differs by only one amino acid; it has a valine residue at position 4. In both peptides, disulfide bonds link Cys1 with Cys13 and Cys7 with Cys19, and the side chain of Asp9 forms an amide bond with the N-terminus. Siamycin II, when dissolved in a 50:50 mixture of DMSO and H2O, yields NOESY spectra with exceptional numbers of cross peaks for a peptide of this size. We have used 335 NOE distance constraints and 13 dihedral angle constraints to generate an ensemble of 30 siamycin II structures; these have average backbone atom and all heavy atom rmsd values to the mean coordinates of 0.24 and 0.52 A, respectively. The peptide displays an unusual wedge-shaped structure, with one face being predominantly hydrophobic and the other being predominantly hydrophilic. Chemical shift and NOE data show that the siamycin I structure is essentially identical to siamycin II. These peptides may act by preventing oligomerization of the HIV transmembrane glycoprotein gp41, or by interfering with interactions between gp41 and the envelope glycoprotein gp120, the cell membrane or membrane-bound proteins [Frèchet, D. et al. (1994) Biochemistry, 33, 42-50]. The amphipathic nature of siamycin II and siamycin I suggests that a polar (or apolar) site on the target protein may be masked by the apolar (or polar) face of the peptide upon peptide/protein complexation.
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