Fattiviracin FV-9

The absolute stereochemistry at the site of attachment of the fatty acid residues to the lactide core of the glycolipids cycloviracin B1 (1) and glucolipsin A (13) has been elucidated as (3R,3'R) by comparison of their 13C NMR data with those of the three possible, differently configured core structures 9, 12, and 14. Moreover, a careful analysis of this set of NMR data allows us to conclude that the structures previously proposed for a seemingly closely related class of antivirally active compounds, i.e., the fattiviracin family, need revision. The key step en route to the symmetrical dilactones 9 and 12 consists of a highly efficient cyclodimerization process which exploits the template effect exerted by potassium cations on the hydroxy acid cyclization precursor. The latter is obtained in excellent overall yield by a sequence involving ring-opening Claisen condensation of pentadecanolide to form the functionalized beta-ketoester 4, asymmetric hydrogenation catalyzed by [(BINAP)RuCl2]2.NEt3, and a beta-selective glycosylation reaction using trichloroacetimidate 6. The unsymmetrical dilactone 14, in contrast, is prepared by a stepwise approach based on a Yamaguchi lactonization as the means to close the macrocyclic ring.

To screen for an effective antiviral compound which acts as a membrane fluidity modulator, dichotomous effects on human immunodeficiency virus type 1 (HIV-1) infection due to different treatments of several glycolipids and lipids were examined. Continuous treatment of infected cells with 40 microg ml(-1) fattiviracin FV-8, a neutral glycolipid isolated from Streptomycetes, inhibited HIV-1 infection by 96%, whereas pretreatment with 400 microg ml(-1) enhanced infectivity 4.7-fold. The glycolipid showed similar effects as glycyrrhizin; it inhibited infection by broad enveloped viruses, blocked cell-cell fusion, reduced the infectivity of treated virions and enhanced susceptibility to viral infection and cell-cell fusion of cells pretreated with high doses of the compound. Suppression and enhancement was correlated with decreased and increased fluidity of plasma membrane of the fattiviracin FV-8-treated cells. Restricted movement of membrane molecules might impede the formation of a wide fusion pore, and therefore be critical to the entry of viruses. Thus, this can be applied as a new strategy to inhibit viral infections.

In 1995, we discovered new antiherpetic antibiotics, called fattiviracins. The producing organism was classified as a strain belonging to Streptomyces microflavus. The strain produced at least 13 fattiviracin derivatives (FV-1 to FV-13). Fattiviracins were obtained as a white amorphous powder, and their molecular weights are in the range of 1400 to 1500. They are readily soluble in water, methanol, pyridine, and DMSO, but insoluble in other organic solvents. Fattiviracins have macrocyclic diesters formed by the binding of two trihydroxy fatty acids and two D-glucose residues in the molecule, and they can be divided into five families according to the length of the fatty acid moiety. Fattiviracins have potent activity against enveloped DNA viruses such as the herpes family, HSV-1, and VZV and enveloped RNA viruses such as influenza A and B viruses, and three strains of HIV-1, with EC(50) values on the order of a few micrograms per milliliter. The biosynthetic pathway of fattiviracins is also becoming clearer. Using bacitracin-resistant strains, enhanced and astringent production of fattiviracin was achieved. Fattiviracin FV-13, which has the longest fatty acid chains in the molecule, was dramatically enhanced by a C(55)-isoprenyl phosphate metabolism. In addition, we have screened various inhibitors of enzymes such as alkaline protease, glucosyltransferase, glucuronidase, phospholipase, deoxyribonuclease, DNA methyltransferase, and DNA topoisomerase. All the inhibitors we discovered are briefly summarized in this paper.