Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Lactams , Leucine , Nitriles , Proline , Ritonavir , Viral Load , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Combinations , Humans , Lactams/adverse effects , Lactams/pharmacology , Lactams/therapeutic use , Leucine/adverse effects , Leucine/pharmacology , Leucine/therapeutic use , Nitriles/adverse effects , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/adverse effects , Proline/pharmacology , Proline/therapeutic use , Recurrence , Ritonavir/adverse effects , Ritonavir/pharmacology , Ritonavir/therapeutic use , Viral Load/drug effectsSubject(s)
Antiviral Agents , Checklist , Drug Interactions , Mass Screening , Antiviral Agents/pharmacology , Checklist/trends , Drug Combinations , Lactams/pharmacology , Leucine/pharmacology , Mass Screening/methods , Mass Screening/trends , Nitriles/pharmacology , Proline/pharmacology , Ritonavir/pharmacologyABSTRACT
Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.
Subject(s)
COVID-19 Drug Treatment , Interleukin-1 Receptor-Associated Kinases , Protein Kinase Inhibitors , Respiratory Distress Syndrome , Animals , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Endothelial Cells , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Isoquinolines/pharmacology , Isoquinolines/therapeutic use , Lactams/pharmacology , Lactams/therapeutic use , Lipopolysaccharides/pharmacology , Lung/pathology , Mice , Protein Kinase Inhibitors/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/prevention & controlABSTRACT
In lab studies, SARS-CoV-2 finds ways to evade key drug. Some of the viral mutations are already found in people.
Subject(s)
COVID-19 Drug Treatment , Coronavirus 3C Proteases , Drug Resistance, Viral , Lactams , Leucine , Nitriles , Proline , Ritonavir , SARS-CoV-2 , Viral Protease Inhibitors , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/genetics , Drug Combinations , Drug Resistance, Viral/genetics , Humans , Lactams/pharmacology , Lactams/therapeutic use , Leucine/pharmacology , Leucine/therapeutic use , Mutation , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/pharmacology , Proline/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Viral Protease Inhibitors/pharmacology , Viral Protease Inhibitors/therapeutic useABSTRACT
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 Treatment , 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 effectsSubject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , COVID-19/virology , Drug Development/trends , Drug Resistance, Viral , Research Personnel , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/supply & distribution , COVID-19/mortality , COVID-19/prevention & control , COVID-19 Vaccines/supply & distribution , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Cytidine/therapeutic use , Drug Approval , Drug Combinations , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Drug Therapy, Combination , Hospitalization/statistics & numerical data , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , Lactams/administration & dosage , Lactams/pharmacology , Lactams/therapeutic use , Leucine/administration & dosage , Leucine/pharmacology , Leucine/therapeutic use , Medication Adherence , Molecular Targeted Therapy , Mutagenesis , Nitriles/administration & dosage , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/administration & dosage , Proline/pharmacology , Proline/therapeutic use , Public-Private Sector Partnerships/economics , Ritonavir/administration & dosage , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/enzymology , SARS-CoV-2/geneticsSubject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , Coronavirus Protease Inhibitors/therapeutic use , Lactams/therapeutic use , Leucine/therapeutic use , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/virology , Clinical Trials as Topic , Coronavirus Protease Inhibitors/administration & dosage , Coronavirus Protease Inhibitors/pharmacology , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Cytidine/therapeutic use , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , Lactams/administration & dosage , Lactams/pharmacology , Leucine/administration & dosage , Leucine/pharmacology , Nitriles/administration & dosage , Nitriles/pharmacology , Proline/administration & dosage , Proline/pharmacology , Ritonavir/administration & dosage , Ritonavir/pharmacology , SARS-CoV-2/drug effects , TabletsABSTRACT
The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Lactams/pharmacology , Leucine/pharmacology , Nitriles/pharmacology , Proline/pharmacology , Antiviral Agents/therapeutic use , Catalytic Domain/drug effects , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/therapeutic use , Humans , Lactams/therapeutic use , Leucine/therapeutic use , Lopinavir/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymologyABSTRACT
The chemical structure of PF-07321332, the first orally available Covid-19 clinical candidate, has recently been revealed by Pfizer. No information has been provided about the interaction pattern between PF-07321332 and its biomolecular counterpart, the SARS-CoV-2 main protease (Mpro). In the present work, we exploited Supervised Molecular Dynamics (SuMD) simulations to elucidate the key features that characterise the interaction between this drug candidate and the protease, emphasising similarities and differences with other structurally related inhibitors such as Boceprevir and PF-07304814. The structural insights provided by SuMD will hopefully be able to inspire the rational discovery of other potent and selective protease inhibitors.
Subject(s)
Antiviral Agents/chemistry , Lactams/chemistry , Leucine/chemistry , Molecular Dynamics Simulation , Nitriles/chemistry , Proline/chemistry , Protease Inhibitors/chemistry , Antiviral Agents/pharmacology , Humans , Lactams/pharmacology , Leucine/pharmacology , Ligands , Nitriles/pharmacology , Peptide Hydrolases/metabolism , Proline/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , SoftwareABSTRACT
SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), was first reported in Wuhan, China, in December 2019. Since then, the virus has stretched its grip to almost all the countries in the world, affecting millions of people and causing enormous casualties. The World Health Organization (WHO) declared COVID-19 a pandemic on March 11, 2019. As of June 12, 2020, almost 7.30 million people have already been infected globally, with 413,000 reported casualties. In the United States alone, 2.06 million people have been infected and 115,000 have succumbed to this pandemic. A multipronged approach has been launched toward combating this pandemic, with the main focus on exhaustive screening, developing efficacious therapies, and vaccines for long-term immunity. Several pharmaceutical companies in collaboration with various academic institutions and governmental organizations have started investigating new therapeutics and repurposing approved drugs so as to find fast and affordable treatments against this disease. The present communication is aimed at highlighting the efforts that are currently underway to treat or prevent SARS-CoV-2 infection, with details on the science, clinical status, and timeline for selected investigational drugs and vaccines. This article is going to be of immense help to the scientific community and researchers as it brings forth all the necessary clinical information of the most-talked-about therapeutics against SARS-CoV-2. All the details pertaining to the clinical status of each therapeutic candidate have been updated as of June 12, 2020.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , COVID-19 Vaccines/pharmacology , Drug Repositioning , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Amides/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , COVID-19/prevention & control , Chloroquine/pharmacology , Clinical Trials as Topic , Cyclopropanes , Drug Evaluation, Preclinical , Humans , Isoindoles , Lactams/pharmacology , Lactams, Macrocyclic , Mice, Transgenic , Proline/analogs & derivatives , Pyrazines/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Sulfonamides/pharmacology , Vaccines, Synthetic/pharmacologyABSTRACT
The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.