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2.
Biomolecules ; 12(7)2022 Jul 05.
Article in English | MEDLINE | ID: covidwho-1917277

ABSTRACT

Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that ultimately led to increased survival of this otherwise deadly condition. Inhibiting the HIV protease impedes the virus from maturing and replicating. With this in mind, since the start of the COVID-19 outbreak, the research for already approved drugs (mainly antivirals) to repurpose for treatment of this disease has increased. Among the drugs tested, saquinavir showed promise in silico and in vitro in the inhibition of the SARS-CoV-2 main protease (3CLpro). Another field for saquinavir repurposing has been in anticancer treatment, in which it has shown effects in vitro and in vivo in several types of cancer, from Kaposi carcinoma to neuroblastoma, demonstrating cytotoxicity, apoptosis, inhibition of cell invasion, and improvement of radiosensibility of cancer cells. Despite the lack of follow-up in clinical trials for cancer use, there has been a renewed interest in this drug recently due to COVID-19, which shows similar pharmacological pathways and has developed superior in silico models that can be translated to oncologic research. This could help further testing and future approval of saquinavir repurposing for cancer treatment.


Subject(s)
COVID-19 , HIV Infections , HIV Protease Inhibitors , Neoplasms , COVID-19/drug therapy , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Humans , Neoplasms/drug therapy , SARS-CoV-2 , Saquinavir/pharmacology , Saquinavir/therapeutic use
3.
Comput Biol Med ; 145: 105523, 2022 06.
Article in English | MEDLINE | ID: covidwho-1814279

ABSTRACT

Starting three decades ago and spreading rapidly around the world, acquired immunodeficiency syndrome (AIDS) is an infectious disease distinct from other contagious diseases by its unique ways of transmission. Over the past few decades, research into new drug compounds has been accompanied by extensive advances, and the design and manufacture of drugs that inhibit virus enzymes is one way to combat the AIDS virus. Since blocking enzyme activity can kill a pathogen or correct a metabolic imbalance, the design and use of enzyme inhibitors is a new approach against viruses. We carried out an in-depth analysis of the efficacy of atazanavir and its newly designed analogs as human immunodeficiency virus (HIV) protease inhibitors using molecular docking. The best-designed analogs were then compared with atazanavir by the molecular dynamics simulation. The most promising results were ultimately found based on the docking analysis for HIV protease. Several exhibited an estimated free binding energy lower than -9.45 kcal/mol, indicating better prediction results than the atazanavir. ATV7 inhibitor with antiviral action may be more beneficial for infected patients with HIV. Molecular dynamics analysis and binding energy also showed that the ATV7 drug had more inhibitory ability than the atazanavir drug.


Subject(s)
Atazanavir Sulfate , HIV Protease Inhibitors , Atazanavir Sulfate/pharmacology , Atazanavir Sulfate/therapeutic use , HIV Protease/chemistry , HIV Protease/metabolism , HIV Protease/therapeutic use , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacology , Molecular Docking Simulation
4.
Antiviral Res ; 202: 105311, 2022 06.
Article in English | MEDLINE | ID: covidwho-1773103

ABSTRACT

Nelfinavir is an HIV protease inhibitor that has been widely prescribed as a component of highly active antiretroviral therapy, and has been reported to exert in vitro antiviral activity against SARS-CoV-2. We here assessed the effect of Nelfinavir in a SARS-CoV-2 infection model in hamsters. Despite the fact that Nelfinavir, [50 mg/kg twice daily (BID) for four consecutive days], did not reduce viral RNA load and infectious virus titres in the lung of infected animals, treatment resulted in a substantial improvement of SARS-CoV-2-induced lung pathology. This was accompanied by a dense infiltration of neutrophils in the lung interstitium which was similarly observed in non-infected hamsters. Nelfinavir resulted also in a marked increase in activated neutrophils in the blood, as observed in non-infected animals. Although Nelfinavir treatment did not alter the expression of chemoattractant receptors or adhesion molecules on human neutrophils, in vitro migration of human neutrophils to the major human neutrophil attractant CXCL8 was augmented by this protease inhibitor. Nelfinavir appears to induce an immunomodulatory effect associated with increasing neutrophil number and functionality, which may be linked to the marked improvement in SARS-CoV-2 lung pathology independent of its lack of antiviral activity. Since Nelfinavir is no longer used for the treatment of HIV, we studied the effect of two other HIV protease inhibitors, namely the combination Lopinavir/Ritonavir (Kaletra™) in this model. This combination resulted in a similar protective effect as Nelfinavir against SARS-CoV2 induced lung pathology in hamsters.


Subject(s)
COVID-19 , HIV Infections , HIV Protease Inhibitors , Animals , COVID-19/drug therapy , Cricetinae , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Lung , Mesocricetus , Nelfinavir/pharmacology , Nelfinavir/therapeutic use , RNA, Viral , Ritonavir/therapeutic use , SARS-CoV-2
5.
J Laryngol Otol ; 135(9): 755-758, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1747302

ABSTRACT

BACKGROUND: There are significant drug-drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. METHOD: All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. RESULTS: A literature search and further cross-referencing yielded a total of seven reports on drug-drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. CONCLUSION: The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.


Subject(s)
Adrenal Cortex Hormones/adverse effects , Cushing Syndrome/chemically induced , HIV Infections/drug therapy , HIV Protease Inhibitors/adverse effects , HIV , Administration, Intranasal , Adrenal Cortex Hormones/administration & dosage , Adult , Cobicistat/administration & dosage , Cobicistat/adverse effects , Drug Interactions , Fluticasone/administration & dosage , Fluticasone/adverse effects , HIV Protease Inhibitors/administration & dosage , Humans , Male , Ritonavir/administration & dosage , Ritonavir/adverse effects
6.
Viruses ; 12(5)2020 04 26.
Article in English | MEDLINE | ID: covidwho-1726007

ABSTRACT

In January 2020, Chinese health agencies reported an outbreak of a novel coronavirus-2 (CoV-2) which can lead to severe acute respiratory syndrome (SARS). The virus, which belongs to the coronavirus family (SARS-CoV-2), was named coronavirus disease 2019 (COVID-19) and declared a pandemic by the World Health Organization (WHO). Full-length genome sequences of SARS-CoV-2 showed 79.6% sequence identity to SARS-CoV, with 96% identity to a bat coronavirus at the whole-genome level. COVID-19 has caused over 133,000 deaths and there are over 2 million total confirmed cases as of April 15th, 2020. Current treatment plans are still under investigation due to a lack of understanding of COVID-19. One potential mechanism to slow disease progression is the use of antiviral drugs to either block the entry of the virus or interfere with viral replication and maturation. Currently, antiviral drugs, including chloroquine/hydroxychloroquine, remdesivir, and lopinavir/ritonavir, have shown effective inhibition of SARS-CoV-2 in vitro. Due to the high dose needed and narrow therapeutic window, many patients are experiencing severe side effects with the above drugs. Hence, repurposing these drugs with a proper formulation is needed to improve the safety and efficacy for COVID-19 treatment. Extracellular vesicles (EVs) are a family of natural carriers in the human body. They play a critical role in cell-to-cell communications. EVs can be used as unique drug carriers to deliver protease inhibitors to treat COVID-19. EVs may provide targeted delivery of protease inhibitors, with fewer systemic side effects. More importantly, EVs are eligible for major aseptic processing and can be upscaled for mass production. Currently, the FDA is facilitating applications to treat COVID-19, which provides a very good chance to use EVs to contribute in this combat.


Subject(s)
Coronavirus Infections/drug therapy , Drug Repositioning , Extracellular Vesicles/chemistry , HIV Protease Inhibitors/administration & dosage , Pneumonia, Viral/drug therapy , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Approval , Drug Delivery Systems , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2
7.
Molecules ; 26(23)2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1555019

ABSTRACT

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM-GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/chemistry , Drug Design , HIV Protease Inhibitors/chemistry , Humans , Protein Binding
9.
Curr HIV Res ; 19(4): 377-382, 2021.
Article in English | MEDLINE | ID: covidwho-1204159

ABSTRACT

BACKGROUND: The World Health Organization (WHO) announced the SARS-COV-2 disease pandemic on March 9, 2020. With the advent of this disease, another health burden was added to about 37.9 million people in the world who are infected with HIV and are suffering from various diseases. These people may be at serious risk of COVID-19. Information about the effects of COVID-19 on people living with HIV, is limited. CASE PRESENTATION: We reported a 61-year-old man who was a known case of HIV from 6 years ago that was being treated with HAART (highly active antiretroviral therapy). He also had a history of Hodgkin's lymphoma from 4 years ago who underwent autologous bone marrow transplantation (BMT) 2 weeks before given referral to our hospital. He complained of weakness, anorexia, and fever. RT-PCR for SARS-COV-2-RNA was positive in his nasopharyngeal and oropharyngeal swab. He was diagnosed with COVID-19 infection and treated with atazanavir. After one week, the patient discharged in a good general state. CONCLUSION: To the best of our knowledge, it is the first report of COVID-19 infection in an HIV positive patient after BMT in Iran. Despite his immunodeficiency, COVID-19 disease had mild manifestations and he had a good prognosis. We hope that our report and that of others can remain promising to doctors and HIV patients cross fingers for COVID-19 recovery.


Subject(s)
Atazanavir Sulfate/therapeutic use , Bone Marrow Transplantation , COVID-19/drug therapy , Comorbidity , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Hodgkin Disease/surgery , Humans , Iran , Male , Middle Aged , SARS-CoV-2 , Treatment Outcome
10.
J Infect Dis ; 224(Supplement_6): S631-S641, 2021 Dec 08.
Article in English | MEDLINE | ID: covidwho-1195718

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding receptor ACE2 and the spike protein priming protease TMPRSS2 are coexpressed in human placentae. It is unknown whether their expression is altered in the context of HIV infection and antiretroviral therapy (ART). METHODS: We compared mRNA levels of SARS-CoV-2 cell-entry mediators ACE2, TMPRSS2, and L-SIGN by quantitative polymerase chain reaction in 105 placentae: 45 from pregnant women with HIV (WHIV) on protease inhibitor (PI)-based ART, 17 from WHIV on non-PI-based ART, and 43 from HIV-uninfected women. RESULTS: ACE2 levels were lower, while L-SIGN levels were higher, in placentae from WHIV on PI-based ART compared to those on non-PI-based ART and to HIV-uninfected women. TMPRSS2 levels were similar between groups. Black race was significantly associated with lower expression of ACE2 and higher expression of L-SIGN. ACE2 levels were significantly higher in placentae of female fetuses. CONCLUSIONS: We identified pregnant women of black race and WHIV on PI-based ART to have relatively lower expression of placental ACE2 than those of white race and HIV-uninfected women. This may potentially contribute to altered susceptibility to COVID-19 in these women, favorably by reduced viral entry or detrimentally by loss of ACE2 protection against hyperinflammation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Cell Adhesion Molecules/metabolism , HIV Infections/blood , Lectins, C-Type/metabolism , Placenta/metabolism , Receptors, Cell Surface/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Adult , Angiotensin-Converting Enzyme 2/genetics , Antiretroviral Therapy, Highly Active , COVID-19/diagnosis , Case-Control Studies , Cell Adhesion Molecules/genetics , Female , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Humans , Lectins, C-Type/genetics , Pregnancy , RNA, Messenger , Real-Time Polymerase Chain Reaction , Receptors, Cell Surface/genetics
11.
J Acquir Immune Defic Syndr ; 85(2): 239-243, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-1165586

ABSTRACT

BACKGROUND: The effectiveness of lopinavir/ritonavir (LPV/r) and chloroquine treatment for COVID-19 has not been verified. METHODS: We conducted a retrospective study to summarize the clinical practices of nonsevere patients with COVID-19 receiving the standard care, LPV/r or chloroquine in Beijing Ditan Hospital from January 20 to March 26, 2020. The main outcome measurements include the changes of cycle threshold values of open reading frame 1 ab (ORF1ab) and nucleocapsid (N) genes by reverse transcriptase-polymerase chain reaction assay from day 1 to 7 after admission for patients receiving standard care or after treatment being initiated for patients receiving either LPV/r or chloroquine. The proportion of developing severe illness, fever duration and the time from symptom onset to chest computer tomography improvement, and negative conversion of nucleic acid were compared. RESULTS: Of the 129 patients included in the study, 59 received the standard care, 51 received LPV/r, and 19 received chloroquine. The demographics and baseline characteristics were comparable among the 3 groups. The median duration of fever, median time from symptom onset to chest computer tomography improvement, and negative conversion of the nucleic acid were similar among the 3 groups. The median increase in cycle threshold values of N and ORF1ab gene for patients receiving LPV/r or chloroquine or the standard care during the treatment course was 7.0 and 8.5, 8.0, and 7.6, 5.0, and 4.0, respectively. These figures were not found significantly different among the 3 groups. CONCLUSIONS: Antiviral therapy using LPV/r or chloroquine seemed not to improve the prognosis or shorten the clinical course of COVID-19.


Subject(s)
Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Lopinavir/therapeutic use , Pneumonia, Viral/drug therapy , Ritonavir/therapeutic use , Adult , Antimalarials/therapeutic use , COVID-19 , Chronic Disease , Coronavirus Infections/complications , Drug Combinations , Female , Fever , HIV Protease Inhibitors/therapeutic use , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Retrospective Studies , Treatment Outcome , Young Adult
12.
Turk J Med Sci ; 51(4): 1624-1630, 2021 08 30.
Article in English | MEDLINE | ID: covidwho-1138801

ABSTRACT

Background/aim: SARS-CoV-2, a ribonucleic acid coronavirus, rapidly spread worldwide within a short timeframe. Although different antiviral, antiinflammatory, and immunomodulatory drugs are used, current evidence is insufficient as to which drug is more efficient. Our study compared favipiravir and lopinavir/ritonavir (LPV/RTV) therapies in inpatient care for coronavirus disease 2019 (COVID-19) pneumonia. Materials and methods: Demographic data, test results, treatments, and latest status of patients receiving inpatient COVID-19 pneumonia therapy were recorded. The initial favipiravir and LPV/RTV receiving groups were compared regarding the need for intensive care units (ICU) and mortality. Logistic regression analysis was performed by including variables showing significant differences as a result of paired comparisons into the model. Results: Of the 204 patients with COVID-19 pneumonia, 59 (28.9%), 131 (64.2%), and 14 were administered LPV/RTV, favipiravir, and favipiravir with LPV/RTV, respectively. No difference was found in age, sex, presence of comorbidity, and tocilizumab, systemic corticosteroid, and plasma therapy use between patients administered with these three different treatment regimens. The mean mortality age of the patients was 71 ± 14.3 years, which was substantially greater than that of the survivors (54.2 ± 15.5 years). Compared with patients administered with LPV/RTV, ICU admission and mortality rates were lower in patients administered with favipiravir. CK-MB, AST, CRP, LDH, and creatinine levels were higher, whereas lymphocyte counts were lower in patients who died. Age, AST, CRP, LDH, and neutrophil counts were higher in patients needing ICU, and eosinophil and lymphocyte counts were significantly lower. Logistic regression analysis showed that favipiravir use independently decreased mortality (p = 0.006). Conclusion: The use of favipiravir was more effective than LPV/RTV in reducing mortality in hospitalized patients with COVID-19.


Subject(s)
Amides/therapeutic use , COVID-19/drug therapy , Lopinavir/therapeutic use , Pyrazines/therapeutic use , Ritonavir/therapeutic use , Aged , Antiviral Agents/therapeutic use , Drug Therapy, Combination/methods , Female , HIV Protease Inhibitors/therapeutic use , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
13.
Eur J Clin Pharmacol ; 77(9): 1297-1307, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1116615

ABSTRACT

AIMS: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications. SUBJECT AND METHOD: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, "SARS-CoV-2," "COVID-19," "antivirals," "therapy"), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19. RESULTS: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir. DISCUSSION: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Clinical Trials as Topic , Drug Combinations , Drug Interactions , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Humans , Nucleosides/analogs & derivatives , Nucleotides/pharmacology , Nucleotides/therapeutic use , Oxygen/blood , SARS-CoV-2
14.
Int J Cardiol ; 324: 255-260, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1065148

ABSTRACT

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Cardiotoxicity/epidemiology , Lopinavir/administration & dosage , Lopinavir/adverse effects , Pharmacovigilance , Ritonavir/administration & dosage , Ritonavir/adverse effects , Aged , Aged, 80 and over , COVID-19/diagnosis , Cardiotoxicity/diagnosis , Drug Combinations , Electrocardiography/drug effects , Electrocardiography/trends , Female , France/epidemiology , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Long QT Syndrome/epidemiology , Male , Middle Aged , Potassium Channel Blockers/administration & dosage , Potassium Channel Blockers/adverse effects
15.
J Chem Inf Model ; 60(12): 5771-5780, 2020 12 28.
Article in English | MEDLINE | ID: covidwho-1065771

ABSTRACT

The novel coronavirus (SARS-CoV-2) has infected several million people and caused thousands of deaths worldwide since December 2019. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. Therefore, in this context, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro, and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a database of ∼4600 natural compounds, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including three natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit a large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals interaction. We also found that Glu166 forms H-bonds to all of the inhibitors. Replacing Glu166 by an alanine residue leads to ∼2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potential drugs inhibiting SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , HIV Protease Inhibitors/chemistry , HIV Protease/metabolism , SARS-CoV-2/drug effects , Amino Acid Sequence , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Biological Products/chemistry , Biological Products/pharmacology , Darunavir/chemistry , Darunavir/pharmacology , Databases, Factual , Drug Design , Glucosides/chemistry , Glucosides/pharmacology , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Peptides/chemistry , Phenols/chemistry , Phenols/pharmacology , Protein Binding , Structure-Activity Relationship , Thermodynamics
16.
Int Immunopharmacol ; 92: 107329, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1014566

ABSTRACT

Interferon Beta-1a (IFN-ß1-a), an immunomodulatory mediator with antiviral effects, has shown in vivo and in vitro activities especially on coronavirus including SARS-CoV-2. COVID-19 defined as the disease caused by infection with SARS-CoV-2. The virus has been illustrated inhibits the production of IFN-ß1-a from inflammatory cells. We conducted a retrospective study of all adult confirmed COVID-19 hospitalized patients who received combination of three doses of 12 million international units of IFN-ß1-a and Lopinavir 400 mg and Ritonavir 100 mg every 12 h (case group) for 14 days besides standard care and age- and sex- matched COVID-19 patients with receiving lopinavir/ritonavir (control group) at Masih Daneshvari Hospital as a designated hospital for COVID-19 between Feb 19 and Apr 30, 2020. Multivariate analysis was done to determine the impact of IFN-ß1-a on outcome and all-cause mortality. 152 cases in IFN-ß1-a group and 304 cases as control group were included. IFN-ß1-a group stayed at hospital longer and required noninvasive ventilation more than control group (13 vs. 6 days, p = 0.001) and (34% vs. 24%, p = 0.04), respectively. During treatment, 57 (12.5%) patients died. The death rate in case and control groups was 11% and 13% respectively. In multivariate analysis, not receiving IFN-ß1-a (HR 5.12, 95% CI: 2.77-9.45), comorbidity (HR 2.28, 95% CI: 1.13-4.60) and noninvasive ventilation (HR 2.77, 95% CI: 1.56-4.93) remained significantly associated with all-cause mortality. In this study, risk of death decreased by using IFN-ß1-a in COVID-19 patients. More clinical study will be necessary to measure efficacy of IFN-ß1-a in COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , HIV Protease Inhibitors/therapeutic use , Interferon-beta/therapeutic use , Lopinavir/therapeutic use , Ritonavir/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Drug Combinations , Female , Humans , Interferon-beta/administration & dosage , Lopinavir/administration & dosage , Male , Middle Aged , Retrospective Studies , Ritonavir/administration & dosage , Young Adult
17.
J Electrocardiol ; 64: 30-35, 2021.
Article in English | MEDLINE | ID: covidwho-972123

ABSTRACT

BACKGROUND: Administration of Hydroxychloroquine and Azithromycin in patients with coronavirus disease 2019 (COVID-19) prolongs QTc corrected interval (QTc). The effect and safety of Lopinavir/Ritonavir in combination with these therapies have seldom been studied. OBJECTIVES: Our aim was to evaluate changes in QTc in patients receiving double (Hydroxychloroquine + Azithromycin) and triple therapy (Hydroxychloroquine + Azithromycin + Lopinavir/Ritonavir) to treat COVID-19. Secondary outcome was the incidence of in-hospital all-cause mortality. METHODS: Patients under treatment with double (DT) and triple therapy (TT) for COVID-19 were consecutively included in this prospective observational study. Serial in-hospital electrocardiograms were performed to measure QTc at baseline and during therapy. RESULTS: 168 patients (±66.2 years old) were included: 32.1% received DT and 67.9% received TT. The mean baseline QTc was 410.33 ms. Patients under DT and TT prolonged QTc interval respect baseline values (p < 0.001), without significant differences between both therapy groups (p = 0.748). Overall, 33 patients (19.6%) had a peak QTc and/or an increase QTc 60 ms from baseline, with a higher prevalence among those with hypokalemia (p = 0.003). All-cause mortality was similar between both strategy groups (p = 0.093) and high risk QTc prolongation was no related to clinical events in this series. CONCLUSIONS: DT and TT prolong the QTc in patients with COVID-19. Addition of Lopinavir/Ritonavir on top of Hydroxychloroquine and Azithromycin did not increase QTc compared to DT.


Subject(s)
Azithromycin/pharmacology , COVID-19/physiopathology , Electrocardiography/drug effects , Hydroxychloroquine/pharmacology , Lopinavir/pharmacology , Ritonavir/pharmacology , Aged , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Drug Therapy, Combination , Female , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Kaplan-Meier Estimate , Lopinavir/therapeutic use , Male , Middle Aged , Prospective Studies , Ritonavir/therapeutic use
18.
Virol J ; 17(1): 190, 2020 11 26.
Article in English | MEDLINE | ID: covidwho-945221

ABSTRACT

BACKGROUND: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. METHODS: We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed. RESULTS: Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 µM concentration. CONCLUSION: Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.


Subject(s)
Coronavirus 3C Proteases/metabolism , HIV Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Cell Survival/drug effects , HEK293 Cells , Humans , Inhibitory Concentration 50 , Proteolysis/drug effects , SARS-CoV-2/drug effects
19.
BMC Infect Dis ; 20(1): 824, 2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917920

ABSTRACT

BACKGROUND: In December 2019, the novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, Hubei Province, China. It rapidly spread and many cases were identified in multiple countries, posing a global health problem. Here, we report the first patient cured of COVID-19 infection in Changsha, China, and the symptoms, diagnosis, treatment, and management of this patient are all described in this report. CASE PRESENTATION: A 57-year-old woman developed cough and fever after returning to Changsha from Wuhan on January 9, 2020. She tested positive for COVID-19 infection, a diagnosis which was supported by chest CT. The patient was treated with lopinavir and ritonavir tablets and interferon alfa-2b injection. A low dose of glucocorticoids was used for a short period to control bilateral lung immune response, and this patient avoided being crushed by cytokine storms that might have occurred. The clinical condition of this patient improved, and a COVID-19 assay conducted on January 25, 2020 generated negative results. This patient recovered and was discharged on January 30, 2020. CONCLUSIONS: Currently, there are numerous reports on COVID-19 infections focusing on the disease's epidemiological and clinical characteristics. This case describes the symptoms, diagnosis, treatment, and management of a patient cured of COVID-19 infection, which may serve as reference for future cases, while further studies are needed.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/drug therapy , Glucocorticoids/therapeutic use , HIV Protease Inhibitors/therapeutic use , Interferon alpha-2/therapeutic use , Lopinavir/therapeutic use , Pneumonia, Viral/drug therapy , Ritonavir/therapeutic use , COVID-19 , China , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Cough , Female , Fever , Humans , Lung/diagnostic imaging , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Tomography, X-Ray Computed , Treatment Outcome
20.
J Mol Graph Model ; 102: 107769, 2021 01.
Article in English | MEDLINE | ID: covidwho-856885

ABSTRACT

Coronavirus outbreak in December 2019 (COVID-19) is an emerging viral disease that poses major menace to Humans and it's a crucial need to find the possible treatment strategies. Spike protein (S2), a envelop glycoprotein aids viral entry into the host cells that corresponds to immunogenic ACE2 receptor binding and represents a potential antiviral drug target. Several drugs such as antimalarial, antibiotic, anti-inflammatory and HIV-protease inhibitors are currently undergoing treatment as clinical studies to test the efficacy and safety of COVID-19. Some promising results have been observed with the patients and also with high mortality rate. Hence, there is a need to screen the best CoV inhibitors using insilico analysis. The Molecular methodologies applied in the present study are, Molecular docking, virtual screening, drug-like and ADMET prediction helps to target CoV inhibitors. The results were screened based on docking score, H-bonds, and amino acid interactions. The results shows HIV-protease inhibitors such as cobicistat (-8.3kcal/mol), Darunavir (-7.4kcal/mol), Lopinavir (-9.1kcal/mol) and Ritonavir (-8.0 kcal/mol), anti-inflammatory drugs such as Baricitinib (-5.8kcal/mol), Ruxolitinib (-6.5kcal/mol), Thalidomide (-6.5kcal/mol), antibiotic drugs such as Erythromycin(-9.0kcal/mol) and Spiramycin (-8.5kcal/mol) molecules have good affinity towards spike protein compared to antimalarial drugs Chloroquine (-6.2kcal/mol), Hydroxychloroquine (-5.2kcal/mol) and Artemisinin (-6.8kcal/mol) have poor affinity to spike protein. The insilico pharmacological evaluation shows that these molecules exhibit good affinity of drug-like and ADMET properties. Hence, we propose that HIVprotease, anti-inflammatory and antibiotic inhibitors are the potential lead drug molecules for spike protein and preclinical studies needed to confirm the promising therapeutic ability against COVID-19.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Computer Simulation , Drug Discovery , Drug Evaluation, Preclinical , Drug Repositioning , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , User-Computer Interface
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