RESUMO
SARS-CoV and SARS-CoV-2 belong to the subfamily Coronaviridae and infect humans, they are constituted by four structural proteins: Spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N), and nonstructural proteins, such as Nsp15 protein which is exclusively present on nidoviruses and is absent in other RNA viruses, making it an ideal target in the field of drug design. A virtual screening strategy to search for potential drugs was proposed, using molecular docking to explore a library of approved drugs available in the DrugBank database in order to identify possible NSP15 inhibitors to treat Covid19 disease. We found from the docking analysis that the antiviral drugs: Paritaprevir and Elbasvir, currently both approved for hepatitis C treatment which showed some of the lowest free binding energy values were considered as repositioning drugs to combat SARS-CoV-2. Furthermore, molecular dynamics simulations of the Apo and Holo-Nsp15 systems were performed in order to get insights about the stability of these protein-ligand complexes.
Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Tratamento Farmacológico da COVID-19 , Ciclopropanos/farmacologia , Endorribonucleases/antagonistas & inibidores , Imidazóis/farmacologia , Lactamas Macrocíclicas/farmacologia , Prolina/análogos & derivados , SARS-CoV-2/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , COVID-19/virologia , Reposicionamento de Medicamentos , Endorribonucleases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Prolina/farmacologia , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/metabolismoRESUMO
Nowadays, the retreatment of patients with Hepatitis C virus (HCV) genotype 3 (GT3) especially cirrhotic, who have already been treated with regimens containing a NS5A inhibitor represents a challenge. Use a novel retreatment option for patients with a difficult approach. We present three case reports of retreatment with a new combination of Direct-acting antivirals (DAAs), Sofosbuvir, Elbasvir/Grazoprevir in patients with GT3 with a previous failure with Sofosbuvir/Ledipasvir. All the cases achieved sustained virologic response (SVR) at week +12 without adverse effects. In our experience, this combo may represent an effective and safe option for these patients.
Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , RNA Viral/genética , Amidas , Benzofuranos/uso terapêutico , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Genótipo , Hepatite C Crônica/virologia , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Quinoxalinas/uso terapêutico , Retratamento , Sofosbuvir/uso terapêutico , Sulfonamidas , Falha de TratamentoRESUMO
BACKGROUND AND AIM: Grazoprevir is an NS3/4A protease inhibitor (PI), while elbasvir is an NS5A inhibitor. We performed this meta-analysis to directly compare grazoprevir plus elbasvir and ribavirin regimen vs. grazoprevir and elbasvir without ribavirin in the treatment of hepatitis C virus genotype 1 infection and to precisely evaluate the efficacy of the latter regimen in cirrhotic, IL28 CC genotype patients and those coinfected with human immunodeficiency virus. MATERIAL AND METHODS: A computer literature search of PubMed, Scopus, EBSCO, Embase, and Cochrane central was conducted. Studies were screened for eligibility. Sustained virologic response (SVR) rates were pooled using OpenMeta[Analyst] software for windows. A subgroup analysis was performed to stratify the treatment efficacy according to the different baseline characteristics of HCV patients. RESULTS: Eight randomized controlled trials (n = 1,297 patients) were pooled in the final analysis. The overall SVR rate was 96.6% with 95% CI [95.5% to 98%]. For cirrhotic patients, the SVR rate was 95.7% with 95% CI [93.9% to 97.5%] and for non-cirrhotic patients, the SVR rate was 97% with 95% CI [95.9% to 98.4%]. Furthermore, the addition of ribavirin (RBV) to the treatment regimen did not significantly improve the SVR (RR 1.003, 95% CI [0.944 to 1.065]). The dual regimen was effective in patient populations with NS3 resistance-associated (RAS). However, this regimen achieved lower SVR rates (< 90%) in patients with NS5A RAS. CONCLUSIONS: We conclude that the 12-week treatment regimen of the fixed dose combination of grazoprevir plus elbasvir achieved high SVR rates in patients with HCV genotype 1 infection. The addition of ribavirin to this regimen did not add a significant benefit.