Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
1.
Nat Struct Mol Biol ; 28(7): 614-625, 2021 07.
Article in English | MEDLINE | ID: covidwho-1550333

ABSTRACT

p97 processes ubiquitinated substrates and plays a central role in cellular protein homeostasis. Here, we report a series of cryo-EM structures of the substrate-engaged human p97 complex with resolutions ranging from 2.9 to 3.8 Å that captured 'power-stroke'-like motions of both the D1 and D2 ATPase rings of p97. A key feature of these structures is the critical conformational changes of the intersubunit signaling (ISS) motifs, which tighten the binding of nucleotides and neighboring subunits and contribute to the spiral staircase conformation of the D1 and D2 rings. In addition, we determined the cryo-EM structure of human p97 in complex with NMS-873, a potent p97 inhibitor, at a resolution of 2.4 Å. The structures showed that NMS-873 binds at a cryptic groove in the D2 domain and interacts with the ISS motif, preventing its conformational change and thus blocking substrate translocation allosterically.


Subject(s)
Adenosine Triphosphate/chemistry , Protein Folding , Proteostasis/physiology , Signal Transduction/physiology , Valosin Containing Protein/metabolism , Acetanilides/pharmacology , Animals , Benzothiazoles/pharmacology , Cryoelectron Microscopy , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum-Associated Degradation/physiology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Conformation , Ubiquitinated Proteins/metabolism , Valosin Containing Protein/antagonists & inhibitors
2.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Article in English | MEDLINE | ID: covidwho-1493345

ABSTRACT

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.


Subject(s)
Benzothiazoles/pharmacology , COVID-19/drug therapy , Oligopeptides/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/genetics , Animals , Benzamidines/chemistry , Benzothiazoles/pharmacokinetics , COVID-19/genetics , COVID-19/virology , Cell Line , Drug Design , Epithelial Cells/drug effects , Epithelial Cells/virology , Esters/chemistry , Guanidines/chemistry , Humans , Lung/drug effects , Lung/virology , Mice , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Oligopeptides/pharmacokinetics , SARS-CoV-2/pathogenicity , Serine Endopeptidases/drug effects , Serine Endopeptidases/ultrastructure , Small Molecule Libraries/pharmacology , Substrate Specificity/drug effects , Virus Internalization/drug effects
3.
Viruses ; 13(8)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1355046

ABSTRACT

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.


Subject(s)
Antiviral Agents/pharmacology , Benzothiazoles/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , SARS-CoV-2/enzymology , SARS-CoV-2/physiology
4.
J Pharm Pharmacol ; 72(11): 1459-1480, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-669796

ABSTRACT

OBJECTIVES: The recent viral pandemic poses a unique challenge for healthcare providers. Despite the remarkable progress, the number of novel antiviral agents in the pipeline is woefully inadequate against the evolving virulence and drug resistance of current viruses. This highlights the urgent need for new and improved vaccines, diagnostics and therapeutic agents to obviate the viral pandemic. KEY FINDINGS: Benzothiazole plays a pivotal role in the design and development of antiviral drugs. This is evident from the fact that it comprises many clinically useful agents. The current review is aimed to provide an insight into the recent development of benzothiazole-based antiviral agents, with a special focus on their structure-activity relationships and lead optimisation. One hundred and five articles were initially identified, and from these studies, 64 potential novel lead molecules and main findings were highlighted in this review. SUMMARY: We hope this review will provide a logical perspective on the importance of improving the future designs of novel broad-spectrum benzothiazole-based antiviral agents to be used against emerging viral diseases.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzothiazoles/pharmacology , Benzothiazoles/therapeutic use , COVID-19/drug therapy , Drug Design , Humans , Pandemics , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...