Evaluation of (1R,2R)-1-(5'-methylfur-3'-yl)propane-1,2,3-triol, a sphydrofuran derivative isolated from a Streptomyces species, as an anti-herpesvirus drug.
(1R,2R)-1-(5'-Methylfur-3'-yl)propane-1,2,3-triol (MFPT), a stable anhydro derivative of sphydrofuran, was obtained from the culture broth of STREPTOMYCES: sp. strain FV60 as an inhibitor of herpes simplex virus type 1 (HSV-1). The compound showed antiherpetic activity with a 50% inhibitory concentration of 1.2 IM in an in vitro assay system. Although the binding of virus to host cells was not inhibited, the penetration of virus into cells was moderately blocked by MFPT. Some of the viruses, once they had penetrated cells, failed to form plaques in the presence of MFPT. When added to the late stages of HSV-1 replication, MFPT also inhibited virus production. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis of isotope-labelled HSV-specific proteins revealed that a protein or proteins with reduced molecular weight (about 120 kDa) was clearly detected in cells treated with MFPT. Western blot analysis with antibodies against three HSV-specific glycoproteins (gB, gC and gD) showed a significant difference in gC synthesis between untreated and MFPT-treated cells. Release of progeny viruses was suppressed by MFPT. Syncytium formation by HSV-1 strain HF was inhibited and small plaques with rounded cells were formed in MFPT-treated cell cultures. When wild-type HSV-1 was serially propagated under the selective pressure of MFPT, resistant virus emerged. MFPT-resistant progeny were accompanied by the formation of plaques with rounded cells. These results, taken together, suggest that MFPT might act by limiting the maturation of HSV-specific glycoproteins, particularly of HSV-1 gC.
Hayashi
K
K
Department of Virology and Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. hayashi9@ms.toyama-mpu.ac.jp
Kawahara
K
K
Nakai
C
C
Sankawa
U
U
Seto
H
H
Hayashi
T
T
D000327:Adsorption; D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004352:Drug Resistance, Microbial; D004591:Electrophoresis, Polyacrylamide Gel; D005663:Furans / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis; D006566:Herpesviridae Infections / Q000382:microbiology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013302:Streptomyces / Q000737:chemistry*; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
C414401:1-(5'-methylfur-3'-yl)propane-1,2,3-triol; D000998:Antiviral Agents; D005663:Furans; D006023:Glycoproteins; D011500:Protein Synthesis Inhibitors; D005990:Glycerol