Cyclosporin A inhibits vaccinia virus replication in vitro

Damaso, Clarissa R.; Keller, Stephen

doi:10.1007/bf01310569

Cited by 37 publications

(49 citation statements)

References 36 publications

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“…3N, asterisk) than in untreated cells (Fig. 3K), which is consistent with previous reports that viral DNA replication is inhibited in VVinfected cells treated with CsA (15,16). Under these conditions, virus progeny production was inhibited to a level 87.4% lower than that in untreated VV-infected BSC-40 cells.…”

Section: Resultssupporting

confidence: 81%

“…2). The immunosuppressant CsA was reported to severely inhibit VV progeny production (15), and this effect was correlated with its ability to bind CypA (16). Therefore, we were most interested in investigating the effect of CsA on CypA rearrangement during infection.…”

Section: Resultsmentioning

confidence: 99%

“…Virus early protein synthesis is slightly affected, and viral DNA accumulation seems to be the primary aim and the rate-limiting step in VV growth in the presence of CsA. However, VV morphogenesis may be particularly targeted (15). CypA was suggested to be involved in the antiviral effect of CsA.…”

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confidence: 99%

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Redistribution of Cyclophilin A to Viral Factories during Vaccinia Virus Infection and Its Incorporation into Mature Particles

Castro

Carvalho

Moussatché

et al. 2003

J Virol

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Cyclophilins are peptidyl-prolyl cis-trans isomerases involved in catalyzing conformational changes and accelerating the rate of protein folding and refolding in several cellular systems. In the present study, we analyzed the expression pattern and intracellular distribution of the cellular isomerase cyclophilin A (CypA) during vaccinia virus (VV) infection. An impressive increase in CypA stability was observed, leading to a practically unchanged accumulation of CypA during infection, although its synthesis was completely inhibited at late times. By confocal microscopy, we observed that CypA went through an intense reorganization in the cell cytoplasm and colocalized with the virosomes late in infection. CypA relocation to viral factories required the synthesis of viral postreplicative proteins, and treatment of infected cells with cyclosporine (CsA) prevented CypA relocation, clearly excluding the virosomes from CypA staining. Immunoelectron microscopy of VVinfected cells showed that CypA was incorporated into VV particles during morphogenesis. Biochemical and electron microscopic assays with purified virions confirmed that CypA was encapsidated within the virus particle and localized specifically in the core. This work suggests that CypA may develop an important role in VV replication.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Redistribution of Cyclophilin A to Viral Factories during Vaccinia Virus Infection and Its Incorporation into Mature Particles

Castro

Carvalho

Moussatché

et al. 2003

J Virol

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“…30 Regarding human immunodeficiency virus type I, in particular, it was suggested that CsA suppresses viral infection through inhibition of the function of CyP, which plays an important role in the life cycle of human immunodeficiency virus type I. 31 The precise molecular mechanism of anti-HCV activity of CsA remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes

et al. 2003

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Persistent infection of hepatitis C virus (HCV) is a major cause of liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Searching for a substance with anti-HCV potential, we examined the effects of a variety of compounds on HCV replication using a HCV subgenomic replicon cell culture system. Consequently, the immunosuppressant cyclosporin A (CsA) was found to have a suppressive effect on the HCV replicon RNA level and HCV protein expression in these cells. CsA also inhibited multiplication of the HCV genome in a cultured human hepatocyte cell line infected with HCV using HCV-positive plasma. This anti-HCV activity of CsA appeared to be independent of its immunosuppressive function. In conclusion, our results suggest that CsA may represent a new approach for the development of anti-HCV therapy. (HEPATOLOGY 2003;38:1282-1288 P ersistent infection with the hepatitis C virus (HCV), identified as the major causative agent of non-A, non-B hepatitis, 1,2 has been closely related to liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. 3 The development of these liver diseases from HCV carriers, an estimated 170 million people throughout the world, is a major public health problem. Effective anti-HCV therapy has been restricted mainly to therapy with interferon (IFN) and a combination of IFN and ribavirin. However, because the virus is not eliminated from approximately one half of HCVinfected patients treated with these agents, 4 alternative approaches to the treatment of HCV infection are needed.Recently, an HCV subgenomic replicon cell culture system has been established in which an HCV subgenomic replicon autonomously replicated in Huh-7 cells (HCV replicon cells). 5 This replicon is composed of the HCV 5Ј-untranslated region containing an internal ribosomal entry site, the neomycin phosphotransferase gene, the encephalomyocarditis virus internal ribosomal entry site, HCV nonstructural proteins (NS) 3 through NS5B; and the HCV 3Ј-untranslated region (Fig. 1A). This system provides a unique tool for studying the mechanisms of HCV replication and screening as well as evaluating anti-HCV compounds. Taking advantage of this feature, we examined the effects of various types of compounds on the replication of HCV using HCV replicon cells established in our laboratory 6 (Miyanari et al., manuscript accepted for publication). Consequently, we found that a well-known immunosuppressant, cyclosporin A (CsA), 7 had a strong suppressive effect on HCV replication in these cells. Moreover, we found suppressive activity of CsA for multiplication of the HCV genome in cultured human hepatocytes infected with HCV. The mechanism of the anti-HCV activity of CsA was also studied. Materials and MethodsCell Culture. Huh-7 and MH-14 cells, HCV replicon cells, were cultured in Dulbecco's modified Eagle medium with 10% fetal bovine serum. PH5CH8 cells were cultured in a 1:1 mixture of Dulbecco's modified Eagle medium and F12 medium supplemented with 100 ng/mL epidermal gro...

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“…The antiviral activity and mechanism of action of CsA was first described for HIV 152 and for VV 153 . CsA inhibits cellular cyclophilins that interact with HIV Gag polyproteins 152 and late proteins of VV 154 , thereby facilitating their correct folding and assembly of replication complexes.…”

Section: Bsas Derived From Fungi: Cyclosporine Statins and Mycophenomentioning

confidence: 99%

Antiviral drug discovery: broad-spectrum drugs from nature

et al. 2015

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, but cannot be converted to PDF. You must view these files (e.g. movies) online.Scheme 1_(structures 1-5)_named.cdx Scheme 2_(structures 6-8)_named.cdx Scheme 3_(structure 9)_named.cdx Scheme 4_(structure 10)_named.cdx Scheme 5_ (structures 11-12) The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with skepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has rebloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, taking particular focus on natural products as promising starting points for antiviral lead development.

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Cyclosporin A inhibits vaccinia virus replication in vitro

Cited by 37 publications

References 36 publications

Redistribution of Cyclophilin A to Viral Factories during Vaccinia Virus Infection and Its Incorporation into Mature Particles

Redistribution of Cyclophilin A to Viral Factories during Vaccinia Virus Infection and Its Incorporation into Mature Particles

Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes

Antiviral drug discovery: broad-spectrum drugs from nature

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