Dataset Information

Targeted Covalent Inhibitors Allosterically Deactivate the DEDDh Lassa Fever Virus NP Exonuclease from Alternative Distal Sites.

ABSTRACT: For using targeted covalent inhibitors (TCIs) as anticancer and antiviral drugs, we establish that the model compounds PCMPS (p-chloromercuriphenyl sulfate) and PCMB (p-chloromercuribenzoate) are inhibitors of the DEDDh family of exonucleases. The underlying mechanism is analyzed by X-ray crystallography, activity/nucleic acid-binding assays, and all-atom molecular dynamics (MD) simulations. The first TCI-complexed structures of a DEDDh enzyme, the Lassa fever virus NP exonuclease (NPexo), are resolved to elucidate that the Cys409 binding site is away from the active site and the RNA-binding lid. The NPexo C409A structures indicate Cys461 as the alternative distal site for obstructing the equally active mutant. All-atom MD simulations of the wild type and mutant NPexos in explicit solvent uncover an allosteric inhibition mechanism that the local perturbation induced by PCMPS sulfonate propagates to impact the RNA-binding lid conformation. Binding assay studies confirm that PCMPS does affect the RNA binding of NPexo. The predicted relative potency between PCMPS and PCMB is also in line with experiments. The structural data and inhibition mechanism established in this work provide an important molecular basis for the drug development of TCIs.

SUBMITTER: Huang KW

PROVIDER: S-EPMC8715546 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundLassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease.Methodology/principal findingsClinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects.Conclusions/significanceLassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF.

Dataset Information

Targeted Covalent Inhibitors Allosterically Deactivate the DEDDh Lassa Fever Virus NP Exonuclease from Alternative Distal Sites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets