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1.
Sci Rep ; 12(1): 2505, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1747189

ABSTRACT

Mpro, the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify Mpro inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to Mpro and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured Mpro and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of Mpro. The most active compound from this chemotype inhibited Mpro in vitro with an IC50 value of 1 µM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to Mpro was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Binding Sites , COVID-19/pathology , COVID-19/virology , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Molecular Conformation , Molecular Docking Simulation , Nitriles/chemistry , Nitriles/metabolism , Nitriles/pharmacology , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/metabolism , Quinazolines/pharmacology , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Virus Replication/drug effects
3.
Int J Mol Sci ; 23(6)2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1742493

ABSTRACT

Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.


Subject(s)
Bone Neoplasms/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/genetics , Organoids/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Androgens/pharmacology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Benzamides/pharmacology , Bone Neoplasms/metabolism , Bone Neoplasms/secondary , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Nitriles/pharmacology , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Transplantation, Heterologous , Virus Internalization
4.
Molecules ; 27(6)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1732134

ABSTRACT

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.


Subject(s)
COVID-19 , Quinolines , COVID-19/drug therapy , Cysteine Endopeptidases/chemistry , Humans , Lactams , Leucine , Molecular Docking Simulation , Nitriles , Peptide Hydrolases , Proline , Quinolines/pharmacology , SARS-CoV-2 , Viral Proteins/metabolism
5.
Nature ; 603(7899): 25-27, 2022 03.
Article in English | MEDLINE | ID: covidwho-1730273

Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Clinical Trials as Topic , Drug Repositioning , Host-Pathogen Interactions/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/economics , Antibodies, Neutralizing/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/economics , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , COVID-19 Vaccines , Cytidine/analogs & derivatives , Cytidine/therapeutic use , Depsipeptides/pharmacology , Depsipeptides/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Drug Combinations , Drug Synergism , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Hospitalization , Humans , Hydroxylamines/therapeutic use , Internationality , Lactams/therapeutic use , Leucine/therapeutic use , Mice , National Institutes of Health (U.S.)/organization & administration , Nitriles/therapeutic use , Peptide Elongation Factor 1/antagonists & inhibitors , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Proline/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors
6.
Reprod Toxicol ; 108: 56-61, 2022 03.
Article in English | MEDLINE | ID: covidwho-1720799

ABSTRACT

Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.


Subject(s)
Antiviral Agents/toxicity , COVID-19/drug therapy , Embryonic Development/drug effects , Fertility/drug effects , Lactams/toxicity , Leucine/toxicity , Nitriles/toxicity , Proline/toxicity , Ritonavir/toxicity , Animals , Drug Combinations , Female , Infertility/chemically induced , Male , Pregnancy , Rabbits , Rats , Rats, Wistar
8.
J Infect Dev Ctries ; 16(1): 63-72, 2022 01 31.
Article in English | MEDLINE | ID: covidwho-1702718

ABSTRACT

INTRODUCTION: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19. METHODOLOGY: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician's criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. RESULTS: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients. CONCLUSIONS: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.


Subject(s)
COVID-19 , Pyrazoles , Pyrimidines , COVID-19/drug therapy , Cohort Studies , Humans , Nitriles , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Treatment Outcome
10.
Bioorg Med Chem Lett ; 62: 128629, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1693835

ABSTRACT

The COVID-19 pandemic continues to be a public health threat. Multiple mutations in the spike protein of emerging variants of SARS-CoV-2 appear to impact on the effectiveness of available vaccines. Specific antiviral agents are keenly anticipated but their efficacy may also be compromised in emerging variants. One of the most attractive coronaviral drug targets is the main protease (Mpro). A promising Mpro inhibitor of clinical relevance is the peptidomimetic nirmatrelvir (PF-07321332). We expressed Mpro of six SARS-CoV-2 lineages (C.37 Lambda, B.1.1.318, B.1.2, B.1.351 Beta, B.1.1.529 Omicron, P.2 Zeta), each of which carries a strongly prevalent missense mutation (G15S, T21I, L89F, K90R, P132H, L205V). Enzyme kinetics reveal that these Mpro variants are catalytically competent to a similar degree as the wildtype. We show that nirmatrelvir has similar potency against the variants as the wildtype. Our in vitro data suggest that the efficacy of the specific Mpro inhibitor nirmatrelvir is not compromised in current COVID-19 variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Lactams , Leucine , Nitriles , Pandemics/prevention & control , Peptide Hydrolases , Proline , Protease Inhibitors , SARS-CoV-2/genetics
11.
Nat Commun ; 13(1): 719, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1692616

ABSTRACT

There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.


Subject(s)
COVID-19/drug therapy , Disease Models, Animal , Lactams/administration & dosage , Leucine/administration & dosage , Nitriles/administration & dosage , Proline/administration & dosage , SARS-CoV-2/drug effects , Viral Protease Inhibitors/administration & dosage , A549 Cells , Administration, Oral , Animals , COVID-19/prevention & control , COVID-19/transmission , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Cricetinae , Humans , Lactams/pharmacokinetics , Leucine/pharmacokinetics , Mesocricetus , Nitriles/pharmacokinetics , Proline/pharmacokinetics , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , SARS-CoV-2/enzymology , SARS-CoV-2/physiology , Vero Cells , Viral Protease Inhibitors/pharmacokinetics , Virus Replication/drug effects
16.
Ann Med ; 54(1): 516-523, 2022 12.
Article in English | MEDLINE | ID: covidwho-1671856

ABSTRACT

BACKGROUND: The coronavirus disease (COVID-19) epidemic has not been completely controlled. Although great achievements have been made in COVID-19 research and many antiviral drugs have shown good therapeutic effects against COVID-19, a simple oral antiviral drug for COVID-19 has not yet been developed. We conducted a meta-analysis to investigate the improvement in mortality or hospitalization rates and adverse events among COVID-19 patients with three new oral antivirals (including molnupiravir, fluvoxamine and Paxlovid). METHODS: We searched scientific and medical databases, such as PubMed, Web of Science, Embase and Cochrane Library for relevant articles and screened the references of retrieved studies on COVID-19. RESULTS: A total of eight studies were included in this study. The drug group included 2440 COVID-19 patients, including 54 patients who died or were hospitalized. The control group included a total of 2348 COVID-19 patients, including 118 patients who died or were hospitalized. The overall odds ratio (OR) of mortality or hospitalization was 0.33 (95% confidence interval [CI], 0.22-0.49) for COVID-19 patients in the drug group and placebo group, indicating that oral antiviral drugs were effective for COVID-19 patients and reduced the mortality or hospitalization by approximately 67%. CONCLUSIONS: This study showed that three novel oral antivirals (molnupiravir, fluvoxamine and Paxlovid) are effective in reducing the mortality and hospitalization rates in patients with COVID-19. In addition, the three oral drugs did not increase the occurrence of adverse events, thus exhibiting good overall safety. These three oral antiviral drugs are still being studied, and the available data suggest that they will bring new hope for COVID-19 recovery and have the potential to be a breakthrough and very promising treatment for COVID-19.KEY MESSAGESMany antiviral drugs have shown good therapeutic effects, and there is no simple oral antiviral drug for COVID-19 patients.Meta-analysis was conducted for three new oral antivirals to evaluate the improvement in mortality or hospitalization rates and adverse events among COVID-19 patients.We focussed on three new oral Coronavirus agents (molnupiravir, fluvoxamine and Paxlovid) and hope to provide guidance for the roll-out of oral antivirals.


Subject(s)
COVID-19 , Fluvoxamine , Antiviral Agents/adverse effects , COVID-19/drug therapy , Cytidine/analogs & derivatives , Drug Combinations , Fluvoxamine/adverse effects , Humans , Hydroxylamines , Lactams , Leucine , Nitriles , Proline , Ritonavir , SARS-CoV-2
18.
Science ; 374(6575): 1586-1593, 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1666355

ABSTRACT

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.


Subject(s)
COVID-19/drug therapy , Lactams/pharmacology , Lactams/therapeutic use , Leucine/pharmacology , Leucine/therapeutic use , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/pharmacology , Proline/therapeutic use , SARS-CoV-2/drug effects , Viral Protease Inhibitors/pharmacology , Viral Protease Inhibitors/therapeutic use , Administration, Oral , Animals , COVID-19/virology , Clinical Trials, Phase I as Topic , Coronavirus/drug effects , Disease Models, Animal , Drug Therapy, Combination , Humans , Lactams/administration & dosage , Lactams/pharmacokinetics , Leucine/administration & dosage , Leucine/pharmacokinetics , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Nitriles/administration & dosage , Nitriles/pharmacokinetics , Proline/administration & dosage , Proline/pharmacokinetics , Randomized Controlled Trials as Topic , Ritonavir/administration & dosage , Ritonavir/therapeutic use , SARS-CoV-2/physiology , Viral Protease Inhibitors/administration & dosage , Viral Protease Inhibitors/pharmacokinetics , Virus Replication/drug effects
19.
Expert Opin Pharmacother ; 23(5): 543-549, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1662063

ABSTRACT

INTRODUCTION: Invasive aspergillosis is associated with high morbidity and mortality in immunocompromised patients. It is now increasingly reported in critically ill patients, including those with respiratory viral infections, such as influenza and COVID-19. Antifungal management is challenging due to diagnostic delay, adverse drug reactions, drug-drug interactions, narrow therapeutic window, and the emergence of resistance. Isavuconazole is the most recent FDA approved azole for the treatment of invasive aspergillosis, with data continuing to accumulate. AREAS COVERED: The authors review the safety and efficacy of isavuconazole in the management of invasive aspergillosis based on the currently available evidence. The authors also report on the structure, mechanism of action, pharmacokinetic properties, in vitro and in vivo studies as well as clinical safety and efficacy reports of isavuconazole since its FDA approval. EXPERT OPINION: Isavuconazole is non-inferior to voriconazole and is a safe, effective, and better tolerated option for the treatment of invasive aspergillosis. It offers several advantages over other antifungal agents, including having a better adverse event profile with respect to hepatotoxicity, neuro-visual toxicity, QTc prolongation, as well as a stable pharmacokinetic profile obviating the need for therapeutic drug monitoring. Further studies are needed to evaluate its performance in prophylaxis against invasive aspergillosis as well as in the treatment of aspergillosis in critically ill patients without underlying cancer or transplant.


Subject(s)
Aspergillosis , COVID-19 , Antifungal Agents/adverse effects , Aspergillosis/chemically induced , Aspergillosis/drug therapy , COVID-19/drug therapy , Delayed Diagnosis , Humans , Nitriles/adverse effects , Pyridines , Triazoles/adverse effects
20.
Antiviral Res ; 198: 105252, 2022 02.
Article in English | MEDLINE | ID: covidwho-1654043

ABSTRACT

We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , Lactams/therapeutic use , Leucine/therapeutic use , Nitriles/therapeutic use , Proline/therapeutic use , SARS-CoV-2/drug effects , Adenosine/analogs & derivatives , Adenosine/therapeutic use , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Animals , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Cytidine/therapeutic use , Humans , Microbial Sensitivity Tests , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Vero Cells , Virus Replication/drug effects
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