• The Korean Journal of Physiology and Pharmacology
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• 제17권5호
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• pp.375-383
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• 2013

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.

• 한국미생물학회:학술대회논문집
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• 한국미생물학회 2005년도 International Meeting of the Microbiological Society of Korea
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• pp.228.1-228
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• 2005

• Bulletin of the Korean Chemical Society
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• 제34권3호
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• pp.837-850
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• 2013

Bovine viral diarrhea virus (BVDV), a major pathogen of cattle, is a well-characterized pestivirus which has been used as a good model virus for HCV. The RNA-dependent RNA polymerase (RdRp) plays a key role in the RNA replication process, thus it has been targeted for antivirus drugs. We employed two-dimensional quantitative structure-activity relationship (2D-QSAR) and molecular field analysis (MFA) to identify the molecular substructure requirements, and the particular characteristics resulted in increased inhibitory activity for the known series of compounds to act as effective BVDV inhibitors. The 2D-QSAR study provided the rationale concept for changes in the structure to have more potent analogs focused on the class of arylazoenamines, benzimidazoles, and acridine derivatives with an optimal subset of descriptors, which have significantly contributed to overall anti-BVDV activity. MFA represented the molecular patterns responsible for the actions of antiviral compound at their receptors. We conclude that the polarity and the polarizability of a molecule play a main role in the inhibitory activity of BVDV inhibitors in the QSAR modeling.

• Bulletin of the Korean Chemical Society
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• 제32권4호
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• pp.1146-1152
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• 2011

The discovery of 2'-spirocyclopropyl-ribocytidine (J. Med. Chem. 2010, 53, 8150-8160) as a potent inhibitor of RNA synthesis by NS5B ($IC_{50}=7.3{\mu}M$), the RNA polymerase encoded by hepatitis C Virus (HCV), has led to the synthesis and biological evaluation of several carbocyclic versions of 2'-spiropropyl-nucleosides. The cyclopentenol intermediate 7 was successfully constructed via ring-closing metathesis (RCM) from divinyl 6. Spirocyclopropanation of enone 8 was effected by using (2-chloroethyl)-dimethylsulfonium iodide and potassium tert-butoxide to form the desired intermediate 9. The synthesized nucleoside analogues 21-24 were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. Among them, the cytosine nucleoside analogue 22 exhibited significant anti-HCV activity ($EC_{50}= 8.2{\mu}M$).

• Bulletin of the Korean Chemical Society
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• 제30권11호
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• pp.2626-2630
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• 2009

2'($\beta$)-Hydroxymethylated adenosine is a potent and selective inhibitor of hepatitis C virus (HCV) replication. It targets the RNA-dependent RNA polymerase of HCV, NS5B. Synthesis and antiviral evaluation of carbocyclic versions are described. The cyclopentene intermediate ($9\beta$) was successfully synthesized through sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis (RCM). Coupling of bases via a Pd(0) catalyst, selective dihydroxylation, and desilylation yielded the target nucleoside analogues. The compounds 17 and 18 were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line and showed moderate antiviral activity with toxicity up to 20.0 and 24.7 ${\mu}g/mL$, respectively.

• 대한임상검사과학회지
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• 제42권1호
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• pp.1-15
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• 2010

Swine influenza virus (SIV) or swine-origin influenza virus (S-OIV) is endemic in swine, and classified into influenza A and influenza C but not influenza B. Swine influenza A includes H1N1, H1N2, H3N1, H3N2 and H2N3 subtypes. Infection of SIV occurs in only swine and that of S-OIV is rare in human. What human can be infected with S-OIV is called as zoonotic swine flu. Pandemic 2009 swine influenza H1N1 virus (2009 H1N1) was emerged in Mexico, America and Canada and spread worldwide. The triple-reassortant H1N1 resulting from antigenic drift was contained with HA, NA and PB1 of human or swine influenza virus, PB2 and PA polymerase of avian influenza virus, and M, NP and NS of swine influenza virus, The 2009 H1N1 enables to transmit to human and swine. The symptoms and signs in human infected with 2009 H1N1 virus are fever, cough and sore throat, pneumonia as well as diarrhea and vomiting. Co-infection with other viruses and bacteria such as Streptococcus pneumoniae can occur high mortality in high-risk population. 2009 H1N1 virus was easily differentiated from seasonal flu by real time RT-PCR which contributed rapid and confirmed diagnosis. The 2009 H1N1 virus was treated with NA inhibitors such as oseltamivir (Tamiflu) and zanamivir (Relenza) but not with adamantanes such as amantadine and rimantadine. Evolution of influenza virus has continued in various hosts. Development of a more effective vaccine against influenza prototypes is needed to protect new influenza infection such as H5 and H7 subtypes to infect to multi-organ and cause high pathogenicity.

• Molecules and Cells
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• 제44권9호
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• pp.688-695
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• 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a global health concern. Various SARS-CoV-2 vaccines have been developed and are being used for vaccination worldwide. However, no therapeutic agents against coronavirus disease 2019 (COVID-19) have been developed so far; therefore, new therapeutic agents are urgently needed. In the present study, we evaluated several hepatitis C virus direct-acting antivirals as potential candidates for drug repurposing against COVID-19. Theses include asunaprevir (a protease inhibitor), daclatasvir (an NS5A inhibitor), and sofosbuvir (an RNA polymerase inhibitor). We found that asunaprevir, but not sofosbuvir and daclatasvir, markedly inhibited SARS-CoV-2-induced cytopathic effects in Vero E6 cells. Both RNA and protein levels of SARS-CoV-2 were significantly decreased by treatment with asunaprevir. Moreover, asunaprevir profoundly decreased virion release from SARS-CoV-2-infected cells. A pseudoparticle entry assay revealed that asunaprevir blocked SARS-CoV-2 infection at the binding step of the viral life cycle. Furthermore, asunaprevir inhibited SARS-CoV-2 propagation in human lung Calu-3 cells. Collectively, we found that asunaprevir displays broad-spectrum antiviral activity and therefore might be worth developing as a new drug repurposing candidate for COVID-19.

• 한국가금학회:학술대회논문집
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• 한국가금학회 2002년도 가을 학술발표논문집
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• pp.59-63
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• 2002

1997년 홍콩 가금시장에서의 H5N1 조류독감바이러스의 발병은 18명의 감염된 사람 중에서 6명의 사람의 생명을 앗아갔다. 이 사건은 조류독감바이러스가 매개체를 통하지 않고 닭에서 바로 사람에게 감염한 처음 있는 사건이다. 홍콩가금시장에서의 역학조사는 H5Nl과 H9N2 조류독감바이러스가 함께 공존한다는 것을 밝혔다. 가금에서는 H5N1과 H9N2 조류독감바이러스가 검출되었다. 우리는 H5N1 조류독감바이러스로부터 자을 방어하는데 H9N2 조류독감바이러스의 역할에 대해 연구했다. H5N1과 H9N2 바이러스의 혼합바이러스를 동시에 자에 접종하면 자은 생존하지 못했다. 그러나, H5N1 조류 독감바이러스감염 이전에 H9N2 조류독감바이러스를 감염한 닭들은 생존할 수 있었다 H9N2 조류 독감바이러스로 감염된 닭으로부터 얻어진 혈청은 H5N1 조류독감바이러스와 교차반응을 일으키지 않는다. H9N2 조류독감바이러스로 감염시킨 닭으로부터 얻어진 T임파구 또는 CD8 T임파구를 감염하지 않은 닭에 주입할 때 닭은 H5N1 조류독감바이러스로부터 생존할 수 있었다. 실험실외 킬러임파구실험은 H9N2 조류독감바이러스로 감염된 닭으로부터 얻어진 T임파구는 H5N1과 H9N2 조류독감바이러스로 감염된 목표세포를 동시에 감지했다. 게다가, 생체내 T임파구의 제거실험은 교차보호면역은 a/b TCR를 가진 CD8 T임파구가 중요한 역할을 하며, a/b TCR (Vbl)형의 T임파구가 목표세포를 감지한다는 것을 증명했다. H9N2 조류독감바이러스에 의한 방어면역은 시간이 지남에 따라 감소를 했고, 감염 100일까지 방어력을 나타냈다. 1997년 조류독감바이러스인 H5N1의 홍콩에서의 발병에 대한 풀리지 않은 것 중의 하나는 약 20%의 조류들이 매우 치사율이 높은 H5N1 독감바이러스를 가지고 있음에도 홍콩가금시장에서의 대부분의 닭들은 건강했다. 얻을 수 있는 정보에 따르면 대부분의 자들은 H5N1조류독감바이러스를 변으로 방출했고, 단지 두 곳의 가금시장에 있는 자들이 질병증상을 보였다. 홍콩가금시장에서 분리된 모든 H5N1 조류독감바이러스를 닭에 감염하면 100%의 치사율을 나타낸다. 바이러스 측면에서의 연구에 따르면, H9N2 조류독감바이러스는 홍콩가금시장에서 두 번째로 많이 분리되었다. H9N2 조류독감바이러스에 대한 연구에 따르면 세 가지 형이 홍콩가금시장에서 검출되었다. 1997년에 가장 많이 분리된 H9N2 조류독감바이러스는 PB1과 PB2가 A/Chicken/HongKong /156/97 (H5N1)과 유전적으로 유사한 A/HongKong/G9/97 (H9N2)형이다. A/Chicken/Hong Kong/156/97(H5N1)의 나머지 유전자는 A/Chicken/HongKong/739/94 (H9N2)와 A/chicken /Hong Kong/G23/97의 유전자와 비슷하다. 하나의 A/Quail/Hong Kong/G1/97은 Quail에서 분리되었고, 두 개의 A/Duck/Hong Kong/Y280/97 (H9N2)은 오리에서 분리되었다. A/Quail/Hong Kong/G1/97 (H9N2)의 6개의 내부유전자는 A/HongKon9/156/97 (H5N1)에 유사하나, A/Duck/ Hongkong/Y280/97 (H9N2)의 유전자는 A/HongKong/156/97 (H5N1)과 유사하지 않다. 킬러임파구는 바이러스로 감염된 목표세포를 MHC에 의존하여 파괴한다. 독감바이러스 특이 킬러임파구는 독감바이러스로 감염된 mice의 폐로부터 독감바이러스를 제거하는데 중요하다고 알려져 있다. 독감바이러스의 HA단백질은 특이 킬러임파구의 주요 목표항원 단백질이 아니다. 내부단백질인 nucleoprotein, polymerase (PB1 PB2, PA), Matrix protein, 그리고 비 구조단백질인 NS1에 대한 특이 킬러임파구의 반응이 사람과 mice에서 보고되었다. 독감바이러스에 대한 mice의 킬러임파구의 인식영역은 제한되어 있다고 알려져 있다. 많은 mice MHC 1은 독감바이러스 단백질의 킬러임파구의 epitope를 표현하지 못한다. 사람 기억킬러임파구는 다양한 종류의 독감바이러스의 단백질을 인식한다고 알려져 있다. 지금까지, 닭에서의 독감바이러스의 킬러임파구에 대한 연구는 되지 않았다.