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Chemical Structure| 1190307-88-0 Chemical Structure| 1190307-88-0

Structure of Sofosbuvir
CAS No.: 1190307-88-0

Chemical Structure| 1190307-88-0

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Sofosbuvir (GS-7977) is an HCV RNA replication inhibitor with an EC50 of 92 nM.

Synonyms: GS-7977; PSI-7977; Resof

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Kupke, Paul ; Adenugba, Akinbami ; Schemmerer, Mathias ; Bitterer, Florian ; Schlitt, Hans J. ; Geissler, Edward K. , et al.

Abstract: Hepatitis E virus (HEV) is a major cause of acute hepatitis globally. Chronic and fulminant courses are observed especially in immunocompromised transplant recipients since administration of ribavirin (RBV) does not always lead to a sustained virol. response. By in vitro stimulation of NK cells through hepatoma cell lines inoculated with a full-length HEV and treatment with RBV, we analyzed the viral replication and cell response to further elucidate the mechanism of action of RBV on immune cells, especially NK cells, in the context of HEV infection. Co-culture of HEV-infected hepatoma cells with PBMCs and treatment with RBV both resulted in a decrease in viral replication, which in combination showed an additive effect. An anal. of NK cell functions after stimulation revealed evidence of reduced cytotoxicity by decreased TRAIL and CD107a degranulation. Simultaneously, IFN-γ production was significantly increased through the IL-12R pathway. Although there was no direct effect on the IL-12R subunits, downstream events starting with TYK-2 and subsequently pSTAT4 were upregulated. In conclusion, we showed that RBV has an immunomodulatory effect on the IL-12R pathway of NK cells via TYK-2. This subsequently leads to an enhanced IFN-γ response and thus, to an additive antiviral effect in the context of an in vitro HEV infection.

Keywords: ribavirin ; hepatitis E virus ; transplantation ; immunosuppression ; NK cells

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Frauke Assmus ; Jean-Sélim Driouich ; Rana Abdelnabi ; Laura Vangeel ; Franck Touret ; Ayorinde Adehin , et al.

Abstract: In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform.

Keywords: COVID-19 ; drug repurposing ; translational medicine ; pandemics ; clinical trials

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Laurent David ; Mark Wenlock ; Patrick Barton ; Andreas Ritzén ;

Abstract: Chameleonic properties, i.e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeabilily and solubility for drug molecules with high MW.We present models ofexperimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113)and one PROTAC(MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics, A linearregression model that predicts chromatographic apparent polarity(EPSA) with a mean unsigned error of 10 A2 was derived based on separate terms for donor, acceptor, and tolal molecular SASA. A good correlation (R'0.92) with an experimental measure of hydrogen bond donor potential, Alog Poa, was found for the mean hydrogenbond donor SASA of the confommational ensemblescaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficlency indices, are introduced. We envislon that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeabilily and solubility.

Keywords: chameleonic properties ; polar surface area ; hydrogen bonding ; molecular dynamics

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Alternative Products

Product Details of Sofosbuvir

CAS No. :1190307-88-0
Formula : C22H29FN3O9P
M.W : 529.45
SMILES Code : C[C@@H](C(OC(C)C)=O)N[P@@](OC1=CC=CC=C1)(OC[C@H]2O[C@@H](N(C(N3)=O)C=CC3=O)[C@](C)(F)[C@@H]2O)=O
Synonyms :
GS-7977; PSI-7977; Resof
MDL No. :MFCD26523124

Safety of Sofosbuvir

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501

Related Pathways of Sofosbuvir

DNA

Isoform Comparison

Biological Activity

Description
Sofosbuvir (GS-7977) is an inhibitor of HCV RNA replication, with an EC50 of 92 nM[1].

In Vitro:

Cell Line
Concentration Treated Time Description References
HEK293 cells 5 μM 24 h To assess the cytotoxicity of Sofosbuvir, results showed no significant cytotoxicity PMC6375661
Huh-7 cells 10 μM 48 h To evaluate the inhibitory effect of Sofosbuvir on HCV replication, results showed significant inhibition of HCV replication PMC6375661
Human fetal neuronal stem cells 2-125 μM 48 h Sofosbuvir significantly inhibited ZIKV infection in human fetal neuronal stem cells with an EC50 of ~32 μM PMC5182171
Jar cells 1-500 μM 72 h Sofosbuvir significantly inhibited ZIKV replication in Jar cells with EC50 values of 1-5 μM and EC90 values of 12-44 μM PMC5182171
Huh-7 cells 1-500 μM 72 h Sofosbuvir significantly inhibited ZIKV replication in Huh-7 cells with EC50 values of 1-5 μM and EC90 values of 12-44 μM PMC5182171
monkey kidney Vero cells 10–20 µM 3 days SOF did not suppress DENV1 production. PMC10889370
hamster kidney BHK-21 cells 5–50 µM 48 h SOF did not suppress the replication of the DENV1 RNA replicon. PMC10889370
Xenopus laevis oocytes 19.2 mM Evaluate the interaction of PSI-6206 with hCNT3 PMC11625470
human hepatic Huh7 cells 5–50 µM 48 h SOF significantly inhibited the replication of the DENV1 RNA replicon in a dose-dependent manner, with approximately 90% inhibition at 50 µM, without cytotoxicity. PMC10889370

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice HCV infection model Oral 30 mg/kg Once daily for 14 days To evaluate the antiviral efficacy of Sofosbuvir in vivo, results showed significant reduction in viral load PMC6375661
Mice ZIKV infection model Oral 33 mg/kg 7 consecutive days Oral administration of Sofosbuvir significantly increased survival rates and prevented weight loss in mice PMC5182171

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT03282474 Hepatitis E|Hepatitis Chronic ... More >>Viral Less << PHASE2 COMPLETED 2019-02-18 Hannover Medical School, Clini... More >>c for Gastroenterology, Hepatology, and Endocrinology, Hanover, Lower Saxony, 30625, Germany|Charité, Campus Virchow-Klinikum, Medical Department, Division of Hepatology and Gastroenterology, Berlin, 13353, Germany|University Medical Center Hamburg-Eppendorf, Center for Internal Medicine, I. Medical Clinic and Polyclinic, Hamburg, 20246, Germany Less <<
NCT02804386 Hepatitis C, Chronic PHASE4 COMPLETED 2018-01-30 Ojha, Duhs, Karachi, Sindh, Pa... More >>kistan Less <<
NCT02783976 HCV Infection COMPLETED 2018-06-20 Cuernavaca, Mexico|Durango, Me... More >>xico|Guadalajara, 44680, Mexico|Guadalajara, Mexico|Mexico City, Mexico|Monterrey, 64460, Mexico Less <<
NCT04664894 Safety Issues COMPLETED 2019-05-30 Liver Center Faisalabad, Faisa... More >>labad, Punjab, Pakistan Less <<
NCT02907996 Hepatitis C Virus COMPLETED 2021-12-09 Yonsei University Wonju Severa... More >>nce Christian Hospital, Wonju, Gangwon-do, 26426, Korea, Republic of|CHA Bundang Medical Center, Sungnam, Gyeonggi-d, 463-712, Korea, Republic of|Hallym University Sacred Heart Hospital, Anyang, 14068, Korea, Republic of|The Catholic University of Korea Bucheon ST. Mary's Hospital, Bucheon-si, 14647, Korea, Republic of|SoonChunHyang University Bucheon Hospital, Bucheon-Si, 420-767, Korea, Republic of|Inje University Haeundae Paik Hospital, Busan, 48108, Korea, Republic of|BongSeng Memorial Hospital, Busan, 48775, Korea, Republic of|Dong-A University Hospital, Busan, 49201, Korea, Republic of|Pusan National University Hospital, Busan, 49241, Korea, Republic of|Kosin University Gospel Hospital, Busan, 49267, Korea, Republic of|Inje University Busan Paik Hospital, Busan, 614-735, Korea, Republic of|Busan St. Mary's Hospital, Busan, Korea, Republic of|Busan Veterans Hospital, Busan, Korea, Republic of|Maryknoll Medical Center, Busan, Korea, Republic of|Changwon Fatima Hospital, Changwon, 51394, Korea, Republic of|Dankook University Hospital, Cheonan, 31116, Korea, Republic of|SoonChunHyang University Cheonan Hospital, Cheonan, 31151, Korea, Republic of|Hallym University ChunCheon Sacred Heart Hospital, Chuncheon-si, 24253, Korea, Republic of|Konkuk University Chungju Hospital, Chungju, 27376, Korea, Republic of|Keimyung University Dongsan Medical Center, Daegu, 41931, Korea, Republic of|Yeungnam University Medical Center, Daegu, 42415, Korea, Republic of|Daegu Catholic University Medical Center, Daegu, 42472, Korea, Republic of|Kyungpook National University Hospital, Daegu, 700-721, Korea, Republic of|Kyungpook national university medical center Chil-Gok, Daegu, 700-721, Korea, Republic of|DaeJeon ST. Mary's Hospital, Daejeon, 301-723, Korea, Republic of|Chungnam National University Hospital, Daejeon, 35015, Korea, Republic of|Daejeon Eulji Medical Center, Daejeon, 35233, Korea, Republic of|GangNeung Asan Hospital, Gangneung, 25440, Korea, Republic of|National Health Insurance Cooperation Ilsan Hospital, Goyang-si, 10444, Korea, Republic of|Dongguk University Ilsan Hospital, Goyang, 10326, Korea, Republic of|Myongji Hospital, Goyang, 10475, Korea, Republic of|Kumi Cha Hospital, Gumi, 39295, Korea, Republic of|Hanyang University Guri Hospital, Guri, 11923, Korea, Republic of|Konkuk University Medical Center, Gwangjin-gu, 05030, Korea, Republic of|Chosun University Hospital, Gwangju, 501-717, Korea, Republic of|Kwangju Christian Hospital, Gwangju, 61661, Korea, Republic of|Dongguk University Gyeongju Hospital, Gyeongju, 38067, Korea, Republic of|Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Korea, Republic of|Chonnam National University Hwasun Hospital, Hwasun, 58128, Korea, Republic of|WonKwang University Hospital, Iksan, 54538, Korea, Republic of|The Catholic University of Korea, Incheon St. Mary's Hospital, Incheon, 21431, Korea, Republic of|Inha University Hospital, Incheon, 22332, Korea, Republic of|Catholic Kwandong University International St. Mary's Hospital, Incheon, 22711, Korea, Republic of|Gachon University Gil Medical Center, Incheon, 405-760, Korea, Republic of|Cheju Halla General Hospital, Jeju-Si, 63127, Korea, Republic of|Chonbuk National University Hospital, Jeonju-si, Korea, Republic of|Presbyterian Medical Center, Jeonju, 54987, Korea, Republic of|Gyeongsang National University Hospital, Jinju, 52727, Korea, Republic of|Seoul National University Bundang Hospital, Seongnam-si, 13620, Korea, Republic of|Korea University Anam Hospital, Seoul, 02841, Korea, Republic of|Seoul National University Hospital, Seoul, 03080, Korea, Republic of|Kangbuk Samsung Hospital, Seoul, 03181, Korea, Republic of|Seoul National University Hospital, Seoul, 03830, Korea, Republic of|SoonChunHyang University Hospital, Seoul, 04401, Korea, Republic of|Hanyang University Hospital, Seoul, 04763, Korea, Republic of|Asan Medical Center, Seoul, 05505, Korea, Republic of|Kangdong Sacred Heart Hospital, Seoul, 05535, Korea, Republic of|Chung-Ang University Hospital, Seoul, 06973, Korea, Republic of|Boramae Medical Center, Seoul, 07061, Korea, Republic of|Ewha Womans University Mokdong Hospital, Seoul, 07985, Korea, Republic of|Inje University Seoul Paik Hospital, Seoul, 100-032, Korea, Republic of|Severance Hospital, Seoul, 120-752, Korea, Republic of|Samsung Medical Center, Seoul, 135-710, Korea, Republic of|Korea University Guro Hospital, Seoul, 152-703, Korea, Republic of|Inje University Sanggye Paik Hospital, Seoul, Korea, Republic of|Nowon Eulji Medical Center, Seoul, Korea, Republic of|The Catholic University of Korea, St. Vincent's Hospital, Suwon-si, 41931, Korea, Republic of|Ajou University Hospital, Suwon, 16499, Korea, Republic of|The Catholic University of Korea Uijeongbu St. Mary's Hospital, Uijeongbu, 11765, Korea, Republic of|Ulsan University Hospital, Ulsan, 44033, Korea, Republic of|Pusan National University Yangsan Hospital, Yangsan, 50612, Korea, Republic of|Yongin Severance Hospital, Yongin, 17046, Korea, Republic of Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

1.89mL

0.38mL

0.19mL

9.44mL

1.89mL

0.94mL

18.89mL

3.78mL

1.89mL

References

 

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