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2.
J Proteome Res ; 19(11): 4690-4697, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-960277

ABSTRACT

SARS-CoV-2 is responsible for the current COVID-19 pandemic. On the basis of our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues (the triphosphates of Sofosbuvir, Alovudine, and AZT) inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). We also demonstrated that a library of additional nucleotide analogues terminate RNA synthesis catalyzed by the SARS-CoV-2 RdRp, a well-established drug target for COVID-19. Here, we used polymerase extension experiments to demonstrate that the active triphosphate form of Sofosbuvir (an FDA-approved hepatitis C drug) is incorporated by SARS-CoV-2 RdRp and blocks further incorporation. Using the molecular insight gained from the previous studies, we selected the active triphosphate forms of six other antiviral agents, Alovudine, Tenofovir alafenamide, AZT, Abacavir, Lamivudine, and Emtricitabine, for evaluation as inhibitors of the SARS-CoV-2 RdRp and demonstrated the ability of these viral polymerase inhibitors to be incorporated by SARS-CoV-2 RdRp, where they terminate further polymerase extension with varying efficiency. These results provide a molecular basis for inhibition of the SARS-CoV-2 RdRp by these nucleotide analogues. If sufficient efficacy of some of these FDA-approved drugs in inhibiting viral replication in cell culture is established, they may be explored as potential COVID-19 therapeutics.


Subject(s)
Antiviral Agents , Betacoronavirus , RNA-Dependent RNA Polymerase , Viral Nonstructural Proteins , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/enzymology , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/virology , Dideoxynucleosides/chemistry , Dideoxynucleosides/metabolism , Dideoxynucleosides/pharmacology , Humans , Pandemics , Pneumonia, Viral/virology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2 , Sofosbuvir/chemistry , Sofosbuvir/metabolism , Sofosbuvir/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
3.
Transpl Infect Dis ; 23(2): e13500, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-916948

ABSTRACT

There is still no consensus on the optimal management of COVID-19 within the general population due to the emerging evidence base. High-risk groups, including kidney transplant recipients living with HIV present unique additional challenges. Here we discuss two kidney transplant recipients living with HIV with SARS-CoV-2 infection and their clinical course, and review the existing literature for this subset of challenging patients.


Subject(s)
Anti-HIV Agents/therapeutic use , COVID-19/therapy , Glucocorticoids/therapeutic use , Graft Rejection/prevention & control , HIV Infections/drug therapy , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Adult , Anti-Bacterial Agents/therapeutic use , Atovaquone/therapeutic use , CD4 Lymphocyte Count , CD4-CD8 Ratio , COVID-19/complications , COVID-19/immunology , Dideoxynucleosides/therapeutic use , Female , HIV Infections/complications , HIV Infections/immunology , HIV-1/genetics , Humans , Immunocompromised Host/immunology , Lamivudine/therapeutic use , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Pneumonia, Pneumocystis/prevention & control , Prednisolone/therapeutic use , RNA, Viral , Raltegravir Potassium/therapeutic use , SARS-CoV-2 , Tacrolimus/therapeutic use , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use
4.
Ann Intern Med ; 173(7): 536-541, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-614702

ABSTRACT

BACKGROUND: The incidence and severity of coronavirus disease 2019 (COVID-19) among HIV-positive persons receiving antiretroviral therapy (ART) have not been characterized in large populations. OBJECTIVE: To describe the incidence and severity of COVID-19 by nucleos(t)ide reverse transcriptase inhibitor (NRTI) use among HIV-positive persons receiving ART. DESIGN: Cohort study. SETTING: HIV clinics in 60 Spanish hospitals between 1 February and 15 April 2020. PARTICIPANTS: 77 590 HIV-positive persons receiving ART. MEASUREMENTS: Estimated risks (cumulative incidences) per 10 000 persons and 95% CIs for polymerase chain reaction-confirmed COVID-19 diagnosis, hospitalization, intensive care unit (ICU) admission, and death. Risk and 95% CIs for COVID-19 diagnosis and hospital admission by use of the NRTIs tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and others were estimated through Poisson regression models. RESULTS: Of 77 590 HIV-positive persons receiving ART, 236 were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to the ICU, and 20 died. The risks for COVID-19 diagnosis and hospitalization were greater in men and persons older than 70 years. The risk for COVID-19 hospitalization was 20.3 (95% CI, 15.2 to 26.7) among patients receiving TAF/FTC, 10.5 (CI, 5.6 to 17.9) among those receiving TDF/FTC, 23.4 (CI, 17.2 to 31.1) among those receiving ABC/3TC, and 20.0 (CI, 14.2 to 27.3) for those receiving other regimens. The corresponding risks for COVID-19 diagnosis were 39.1 (CI, 31.8 to 47.6), 16.9 (CI, 10.5 to 25.9), 28.3 (CI, 21.5 to 36.7), and 29.7 (CI, 22.6 to 38.4), respectively. No patient receiving TDF/FTC was admitted to the ICU or died. LIMITATION: Residual confounding by comorbid conditions cannot be completely excluded. CONCLUSION: HIV-positive patients receiving TDF/FTC have a lower risk for COVID-19 and related hospitalization than those receiving other therapies. These findings warrant further investigation in HIV preexposure prophylaxis studies and randomized trials in persons without HIV. PRIMARY FUNDING SOURCE: Instituto de Salud Carlos III and National Institutes of Health.


Subject(s)
Antiretroviral Therapy, Highly Active , Coronavirus Infections/epidemiology , HIV Infections/drug therapy , Pneumonia, Viral/epidemiology , Adenine/analogs & derivatives , Adult , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Dideoxynucleosides , Drug Combinations , Emtricitabine , Female , HIV Infections/mortality , Hospitalization/statistics & numerical data , Humans , Incidence , Intensive Care Units/statistics & numerical data , Lamivudine , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Severity of Illness Index , Spain/epidemiology , Tenofovir
5.
Antiviral Res ; 180: 104857, 2020 08.
Article in English | MEDLINE | ID: covidwho-602131

ABSTRACT

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2' or 3' modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses' exonuclease activity. We examined these nucleotide analogues for their ability to be incorporated by the RdRps in the polymerase reaction and to prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (triphosphates of Carbovir, Ganciclovir, Stavudine and Entecavir; 3'-OMe-UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2'-OMe-UTP), and 3 did not terminate the polymerase reaction (2'-F-dUTP, 2'-NH2-dUTP and Desthiobiotin-16-UTP). The coronaviruses possess an exonuclease that apparently requires a 2'-OH at the 3'-terminus of the growing RNA strand for proofreading. In this study, all nucleoside triphosphate analogues evaluated form Watson-Crick-like base pairs. The nucleotide analogues demonstrating termination either lack a 2'-OH, have a blocked 2'-OH, or show delayed termination. Thus, these nucleotide analogues are of interest for further investigation to evaluate whether they can evade the viral exonuclease activity. Prodrugs of five of these nucleotide analogues (Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA-approved medications for treatment of other viral infections, and their safety profiles are well established. After demonstrating potency in inhibiting viral replication in cell culture, candidate molecules can be rapidly evaluated as potential therapies for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/virology , Nucleotides/pharmacology , Pneumonia, Viral/virology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS Virus/enzymology , Severe Acute Respiratory Syndrome/virology , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Betacoronavirus/enzymology , Betacoronavirus/genetics , COVID-19 , Cidofovir/chemistry , Cidofovir/pharmacology , Cidofovir/therapeutic use , Coronavirus Infections/drug therapy , Dideoxynucleosides/chemistry , Dideoxynucleosides/pharmacology , Dideoxynucleosides/therapeutic use , Ganciclovir/chemistry , Ganciclovir/pharmacology , Ganciclovir/therapeutic use , Guanine/analogs & derivatives , Guanine/chemistry , Guanine/pharmacology , Guanine/therapeutic use , Nucleotides/chemistry , Nucleotides/therapeutic use , Pandemics , Pneumonia, Viral/drug therapy , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/therapeutic use , RNA, Viral/antagonists & inhibitors , RNA, Viral/biosynthesis , SARS Virus/genetics , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Stavudine/chemistry , Stavudine/pharmacology , Stavudine/therapeutic use , Valganciclovir/chemistry , Valganciclovir/pharmacology , Valganciclovir/therapeutic use
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