Biology subjects

Cousins, D.

Publications and source records attributed to Cousins, D..

5 recordsLinked to original sources

bioRxiv2025

A Structure-Based Computational Pipeline for Broad-Spectrum Antiviral Discovery

The rapid emergence of viruses with pandemic potential continues to pose a threat to public health worldwide. With the typical drug discovery pipeline taking an average of 5-10 years to reach clinical readiness, there is an urgent need for strategies to develop broad-spectrum antivirals that can target multiple viral family members and variants of concern. We present a structure-based computational pipeline designed to identify and evaluate broad-spectrum inhibitors across viral family members for a given target in order to support spectrum breadth assessment and prioritization in lead optimization programs. This pipeline comprises three key steps: (1) an automated search to identify viral sequences related to a specified target construct, (2) pose prediction leveraging any available structural data, and (3) scoring of protein-ligand complexes to estimate antiviral activity breadth. The pipeline is implemented using the drugforge package: an open-source toolkit for structure-based antiviral discovery. To validate this framework, we retrospectively evaluated two overlapping datasets of ligands bound to the SARS-CoV-2 and MERS-CoV main protease (Mpro), observing useful predictive power with respect to experimental binding affinities. Additionally, we screened known SARS-CoV-2 Mpro inhibitors against a panel of human and non-human coronaviruses, demonstrating the potential of this approach to assess broad-spectrum antiviral activity. Our computational strategy aims to accelerate the identification of antiviral therapies for current and emerging viruses with pandemic potential, contributing to global preparedness for future outbreaks.

bioinformatics↗

bioRxiv2025

Discovery of orally bioavailable Zika and West Nile Virus antiviral compounds targeting the NS2B-NS3 protease

Flaviviruses are a class of pathogenic viruses with pandemic potential that are typically transmitted via infected arthropods. In addition, Zika virus is sexually transmissible and causes congenital malformations if infection occurs during pregnancy. Although over 1.5 million people were infected during the 2015-2016 Zika outbreak, to date, there are no clinical-stage vaccines or antivirals. Herein, we report the discovery of potent inhibitors of the Zika virus NS2B-NS3 protease that also show activity against the West Nile virus NS2B-NS3 protease. Starting from a crystallographic fragment screen, we employed a pharmacophore approach coupled with high-throughput library chemistry to elaborate fragments in the active site. Potent, metabolically stable, non-covalent, non-peptidomimetic inhibitors were identified with antiviral activity in vitro. The lead compound was progressed to a three-day Zika virus challenge study in AG129 mice, where it displayed significant viral RNA load reduction in both mouse plasma and spleen.

microbiology↗

bioRxiv2024

Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.

microbiology↗

bioRxiv2024

Chromosome structural rearrangements in invasive haplodiploid ambrosia beetles revealed by the genomes of Euwallacea fornicatus and Euwallacea similis (Coleoptera, Curculionidae, Scolytinae)

Bark and ambrosia beetles are among the most ecologically and economically damaging introduced plant pests worldwide, with life history traits including polyphagy, haplodiploidy, inbreeding polygyny and symbiosis with fungi contributing to their dispersal and impact. Species vary in host tree ecologies, with many attacking stressed or recently dead trees, such as the globally distributed E. similis (Ferrari). Other species, like the Polyphagous Shot Hole Borer (PSHB) Euwallacea fornicatus (Eichhoff), can attack over 680 host plants and is causing considerable economic damage in several countries worldwide. Despite their notoriety, publicly accessible genomic resources for Euwallacea Hopkins species are scarce, hampering better understanding of their invasive capabilities as well as modern control measures, surveillance and management. Using a combination of long and short read sequencing platforms we assembled and annotated high quality (BUSCO > 98% complete) chromosome level genomes for these species. Comparative macro-synteny analysis showed an increased number of chromosomes in the haplodiploid inbreeding species of Euwallacea compared to diploid outbred species, due to fission events. This suggests that life history traits can impact chromosome structure. Further, the genome of E. fornicatus had a higher relative proportion of repetitive elements, up to 17% more, than E. similis. Additionally, metagenomic assembly pipelines identified microbiota associated with both species including Fusarium fungal symbionts and a novel Wolbachia strain. These novel genomes of haplodiploid inbreeding species will contribute to the understanding of how life history traits are related to their evolution and will contribute to the management of these invasive pests. SignificanceScolytinae are significant forestry pests around the world and commonly translocated due to human trade of wood and plant products. Life history traits including inbreeding and haplodiploidy are attributed to their successful establishment in novel environments. Euwallacea fornicatus is widely distributed and attacks a wide variety of live host trees. This study reports the genome of this species and for, E. similis, which colonises dead host trees. The genome assemblies presented herein are highly complete and scaffolded to pseudo-chromosomal level. Comparative analyses of these genomes and of other Scolytinae highlight significant chromosomal rearrangements between haplodiploid inbreeding Euwallacea and diploid outbreeding scolytinae species. Higher relative proportions of transposable elements were identified E. fornicatus, which may promote the species ability to attack live host trees. These genomes are the first for haplodiploid beetles and will contribute to the understanding of evolution of life history traits and the management of invasive insects.

genomics↗

bioRxiv2018

Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium.

Asthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. We undertook genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma and healthy controls. We identified 49,903 regions exhibiting differential H3K27ac enrichment in asthma, clustered at genes associated with type-2-high asthma (CLCA1) and epithelial processes (EMT). Asthma dramatically influenced the BEC enhancer landscape and we identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (NOX4). We integrated published protein, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, we used a CRISPR-based approach to recapitulate the H3K27ac-asthma landscape in vitro and provide proof of principal that asthma-associated gene expression (SERPINB2) is driven in part by aberrant histone acetylation, validating the combination of genome-wide and epigenome-editing approaches in deciphering the molecular mechanisms underlying asthma pathogenesis.

genomics↗