Study of structure-activity correlation in destruxins, a class of cyclodepsipeptides possessing suppressive effect on the generation of hepatitis B virus surface antigen in human hepatoma cells.

A new destruxin [destruxin E2 chlorohydrin] was isolated from the culture medium of Metarrhizium anisopliae and its structure was determined by NMR spectroscopy and mass spectrometry. As compared with other destruxins, the new destruxin showed a lower suppressive activity on the production of hepatitis B virus surface antigen in human hepatoma Hep3B cells. NMR study coupled with molecular modeling by computer graphics has revealed that the hydrophobicity nature of the convex surface characteristic of all destruxin molecules plays an important role in their biological activity.

Conformational study of two linear hexapeptides by two-dimensional NMR and computer-simulated modeling: implication for peptide cyclization in solution.

Two linear peptides, D-leucyl-L-prolyl-L-isoleucyl-L-valyl-L-alanyl-beta-alanine (I) and D-leucyl-L-prolyl-L-isoleucyl-L-valyl-N-methyl-L-alanyl-beta-alanine (II), whose sequences were designed from protodestruxin and desmethyldestruxin B by replacing D-leucic acid with D-leucine, two cyclic hexadepsipeptides with insecticidal and immunodepressant activities, have been found to be cyclized in unusually high yields (>85%). In order to gain insight into the conformation and the relative flexibility of different constituent residues in these linear peptides, we have applied various techniques of 2D-NMR spectroscopy coupled with dynamic simulated annealing by computer modeling to establish the solution conformations of these two linear peptides. Based on the derived structures, it is found that the distances between N- and C-terminal residues of both peptides are short enough to facilitate the cyclization, thus collaborating the observation of favorable cyclization yields for both linear peptides.

Conformation of polymyxin B analogs in DMSO from NMR spectra and molecular modeling.

The tertiary structures of two polymyxin analogues: [formula: see text] and [formula: see text] in DMSO, from solid-phase peptide synthesis and aerobic oxidation were determined from two-dimensional NMR spectra and distance geometry calculations followed by restrained molecular dynamics simulation. The backbone of peptide I had a rectangular shape stabilized by at least two hydrogen bonds and the hydrophilic side chains of five lysine residues, and the hydrophobic side chains of Phe and Leu resided at both sides to form an amphiphilic molecule. This amphiphilic structure of I is likely to interact with lipid A mainly via a hydrophobic interaction. Compared with I, peptide II, which lacks three N-terminal amino-acid residues, exhibits neither amphiphilic property nor binding ability with lipid A.

The novel desmethyldestruxin B2, from Metarhizium anisopliae, that suppresses hepatitis B virus surface antigen production in human hepatoma cells.

We have examined the antiviral activity of a crude extract prepared from the culture medium of the fungus Metarhizium anisopliae. Eight active destruxins were identified which showed strong suppressive effect on the production of the hepatitis B surface antigen (HBsAg) in human hepatoma Hep3B cells. One new compound, desmethyldestruxin B2 [1], was isolated from M. anisopliae. This structure was determined based on its nmr and mass spectral data.