ABSTRACT
Evidence indicates that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in its replication, and cyclophilin inhibitors represent a new class of anti-HCV agents. We have established an efficient synthetic methodology to generate FR901459 derivatives via N, O-acyl migration reaction while avoiding total synthesis. Through a detailed structure-activity relationship study, we improved anti-HCV activity while decreasing immunosuppressive activity. Additionally, we discovered the importance of substitution at the 3 position for not only improving anti-HCV activity but also pharmacokinetic profile. Finally, by striking an appropriate balance between potency, solubility, and permeability, we discovered ASP5286 (13) as a potential clinical candidate for anti-HCV therapy.
Subject(s)
Antiviral Agents/pharmacology , Cyclophilins/antagonists & inhibitors , Drug Discovery , Hepacivirus/drug effects , Immunosuppressive Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
In search for new anti-varicella zoster virus (VZV) compounds with new mechanism of action, we applied a DNA hybridization assay (dot blot method) for screening. Using this method, we screened microbial products and found the polyether compound CP-44161 from the culture broth of an actinomycete strain. CP-44161 was previously reported as an anticoccidal agent, but there has been no claim of its antiviral activities. CP-44161 showed strong anti-VZV activity against pOka strain by plaque reduction assay. Moreover, CP-44161 showed lower cytotoxicity than other antiviral polyethers, such as monensin and nigericin. Its better safety margin and strong anti-VZV properties make it a good candidate for a new anti-VZV agent.
Subject(s)
Antiviral Agents/pharmacology , Furans/pharmacology , Herpesvirus 3, Human/drug effects , Pyrans/pharmacology , Actinomycetales/chemistry , Actinomycetales/classification , Actinomycetales/metabolism , Bridged-Ring Compounds , Carbohydrate Sequence , Cell Line, Tumor , Cytopathogenic Effect, Viral/drug effects , DNA, Viral/chemistry , DNA, Viral/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Ethers , Fermentation , Humans , Immunoblotting , Indicators and Reagents , Molecular Sequence DataABSTRACT
In the previous study, we discovered a polyether antibiotic CP-44161, which was reported earlier as an anticoccidal agent, as an anti-varicella zoster virus compound. In this study, we demonstrated that CP-44161 had a very strong and broad anti-herpes virus activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. To determine the antiviral activity of CP-44161 in vivo, we examined its effect on the cutaneous HSV-2 infection model in Balb/c mice. CP-44161 showed inhibitory effect on lesion development as well as acyclovir (ACV) when the treatment was started from day 3. Meanwhile, in case the start of treatment was delayed until day 4, when ACV was no longer effective, the effectiveness of CP-44161 still remained. In this model, CP-44161 also showed inhibitory effect on the proliferation of HSV-2 DNA in dorsal root ganglia. This is the first article to report that polyether antibiotics can be effective on viral infection in vivo.
Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Furans/pharmacology , Furans/therapeutic use , Herpes Simplex/drug therapy , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Pyrans/pharmacology , Pyrans/therapeutic use , Acyclovir/therapeutic use , Animals , Bridged-Ring Compounds , Carbohydrate Conformation , Carbohydrate Sequence , Cell Survival/drug effects , Chlorocebus aethiops , DNA, Viral/analysis , DNA, Viral/biosynthesis , DNA, Viral/genetics , Ethers , Female , Ganglia, Spinal/chemistry , Ganglia, Spinal/virology , Herpes Simplex/virology , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Vero CellsABSTRACT
Disodium cromoglycate (DSCG) is one of the safest drugs for the prevention of bronchial asthma and allergic rhinitis attacks. The effect of DSCG on acute upper respiratory tract viral infection is still controversial. Here we investigated DSCG inhibition of influenza virus infection in vivo and in vitro. In vivo effects of DSCG on viral infection were assessed using a murine model of respiratory tract infection. Intranasal administration of DSCG protected mice from death induced by infection with influenza virus A/PR/8/34. We analyzed DSCG anti-viral effects in vitro by either (i) treating cells prior to viral adsorption, (ii) treating cells concurrently with viral adsorption, or (iii) treating cells after viral adsorption. DSCG treatment of cells during or after, but not before, viral adsorption significantly inhibited influenza viral infection, indicating DSCG acts on events late in viral infection. DSCG exerts anti-influenza effect both in vitro and in vivo at the doses compatible with treatment for asthma. DSCG marginally inhibited influenza viral neuraminidase and membrane fusion functions, suggesting that DSCG inhibition of viral neuraminidase and fusion activities may partially mediate this anti-influenza effect. Our results indicate that treatment of patients including children with DSCG may take advantages for prevention from influenza virus infection.
