Biomaterial Database

The Nucleoside/Nucleotide Analogs Tenofovir and Emtricitabine Are Inactive against SARS-CoV-2. 2022

Joy Y Feng, and Venice Du Pont, and Darius Babusis, and Calvin J Gordon, and Egor P Tchesnokov, and Jason K Perry, and Vincent Duong, and Arya Vijjapurapu, and Xiaofeng Zhao, and Julie Chan, and Cal Cohen, and Kavita Juneja, and Tomas Cihlar, and Matthias Götte, and John P Bilello

Gilead Sciences, Inc., Foster City, CA 94404, USA.

The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.

UI	MeSH Term	Description	Entries
D009705	Nucleosides	Purine or pyrimidine bases attached to a ribose or deoxyribose. (From King & Stansfield, A Dictionary of Genetics, 4th ed)	Nucleoside,Nucleoside Analog,Nucleoside Analogs,Analog, Nucleoside,Analogs, Nucleoside
D009711	Nucleotides	The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed)	Nucleotide
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000068679	Emtricitabine	A deoxycytidine analog and REVERSE TRANSCRIPTASE INHIBITOR with antiviral activity against HIV-1 and HEPATITIS B viruses. It is used to treat HIV INFECTIONS.	Beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine,Coviracil,Emtriva,Beta L 2',3' dideoxy 5 fluoro 3' thiacytidine
D000068698	Tenofovir	An adenine analog REVERSE TRANSCRIPTASE INHIBITOR with antiviral activity against HIV-1 and HEPATITIS B. It is used to treat HIV INFECTIONS and CHRONIC HEPATITIS B, in combination with other ANTIVIRAL AGENTS, due to the emergence of ANTIVIRAL DRUG RESISTANCE when it is used alone.	(R)-9-(2-phosphonylmethoxypropyl)adenine,9-(2-Phosphonomethoxypropyl)adenine,9-(2-Phosphonylmethoxypropyl)adenine,9-(2-Phosphonylmethoxypropyl)adenine, (+-)-isomer,9-(2-Phosphonylmethoxypropyl)adenine, (R)-isomer - T357098,9-(2-Phosphonylmethoxypropyl)adenine, (S)-isomer,9-PMPA (tenofovir),Tenofovir Disoproxil,Tenofovir Disoproxil Fumarate,Viread,Disoproxil Fumarate, Tenofovir,Disoproxil, Tenofovir,Fumarate, Tenofovir Disoproxil
D000086402	SARS-CoV-2	A species of BETACORONAVIRUS causing atypical respiratory disease (COVID-19) in humans. The organism was first identified in 2019 in Wuhan, China. The natural host is the Chinese intermediate horseshoe bat, RHINOLOPHUS affinis.	2019 Novel Coronavirus,COVID-19 Virus,COVID19 Virus,Coronavirus Disease 2019 Virus,SARS Coronavirus 2,SARS-CoV-2 Virus,Severe Acute Respiratory Syndrome Coronavirus 2,Wuhan Coronavirus,Wuhan Seafood Market Pneumonia Virus,2019-nCoV,2019 Novel Coronaviruses,COVID 19 Virus,COVID-19 Viruses,COVID19 Viruses,Coronavirus 2, SARS,Coronavirus, 2019 Novel,Coronavirus, Wuhan,Novel Coronavirus, 2019,SARS CoV 2 Virus,SARS-CoV-2 Viruses,Virus, COVID-19,Virus, COVID19,Virus, SARS-CoV-2,Viruses, COVID19
D000093485	COVID-19 Drug Treatment	The use of DRUGS to treat COVID19 or its symptoms.	COVID-19 Drug Therapy,COVID19 Drug Therapy,COVID19 Drug Treatment,Coronavirus Disease 2019 Drug Treatment,Coronavirus Disease-19 Drug Treatment,COVID 19 Drug Therapy,COVID 19 Drug Treatment,COVID-19 Drug Therapies,COVID19 Drug Therapies,COVID19 Drug Treatments,Coronavirus Disease 19 Drug Treatment,Drug Therapy, COVID-19,Drug Therapy, COVID19,Therapy, COVID-19 Drug,Therapy, COVID19 Drug,Treatment, COVID-19 Drug
D012324	RNA-Dependent RNA Polymerase	An enzyme that catalyses RNA-template-directed extension of the 3'- end of an RNA strand by one nucleotide at a time, and can initiate a chain de novo. (Enzyme Nomenclature, 1992, p293)	Nucleoside-Triphosphate:RNA Nucleotidyltransferase (RNA-directed),RNA Replicase,RNA-Dependent RNA Replicase,RNA-Directed RNA Polymerase,RNA Dependent RNA Polymerase,RNA Dependent RNA Replicase,RNA Directed RNA Polymerase,RNA Polymerase, RNA-Dependent,RNA Polymerase, RNA-Directed,RNA Replicase, RNA-Dependent,Replicase, RNA,Replicase, RNA-Dependent RNA
D012367	RNA, Viral	Ribonucleic acid that makes up the genetic material of viruses.	Viral RNA
D015497	HIV-1	The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte.	Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human