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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
Sci Rep ; 10(1): 16986, 2020 10 12.
Article in English | MEDLINE | ID: covidwho-851312

ABSTRACT

We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein-ligand complexes and suggest the possibilities of further drug optimisations.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/metabolism , Drug Repositioning/methods , HIV Protease Inhibitors/pharmacology , Pneumonia, Viral/drug therapy , Viral Nonstructural Proteins/metabolism , Betacoronavirus/metabolism , Binding Sites/drug effects , Biophysical Phenomena , COVID-19 , Catalytic Domain/drug effects , Computational Biology , Coronavirus 3C Proteases , Darunavir/metabolism , Darunavir/pharmacology , HIV Protease Inhibitors/metabolism , Humans , Indinavir/metabolism , Indinavir/pharmacology , Lopinavir/metabolism , Lopinavir/pharmacology , Molecular Dynamics Simulation , Nelfinavir/metabolism , Nelfinavir/pharmacology , Pandemics , Ritonavir/metabolism , Ritonavir/pharmacology , SARS-CoV-2 , Saquinavir/metabolism , Saquinavir/pharmacology
10.
Viruses ; 12(8)2020 07 26.
Article in English | MEDLINE | ID: covidwho-671037

ABSTRACT

COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (MPRO) inhibitors that fit in the catalytic binding site of SARS CoV-2 MPRO. Several selected structures are NAD-like derivatives, suggesting a relevant role of these molecules in the modulation of SARS CoV-2 infection in conditions of cell chronic oxidative stress. Increased catabolism of NAD(H) during protein ribosylation in the DNA damage repair process may explain the greater susceptibility of the elderly population to the acute respiratory symptoms of COVID-19. The molecular modelling studies proposed herein agree with this hypothesis.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , NAD/metabolism , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Aging/metabolism , Binding Sites , COVID-19 , Computer Simulation , Coronavirus 3C Proteases , Coronavirus Infections/metabolism , Coronavirus Infections/virology , DNA Damage , Drug Repositioning , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Humans , Models, Molecular , Molecular Docking Simulation , Oxidation-Reduction , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , SARS-CoV-2
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