Human disease caused by pathogenic infectious agents is a worldwide burden, often accompanied with significant unmet medical needs. Novel and/or improved therapeutic options are required both for numerous existing diseases caused by adventitious micro-organisms, and new diseases arising from emerging pathogens, e.g. SARS-CoV-2: the aetiological agent of Covid-19.
Sygnature’s integrated medicinal chemistry, DMPK and bioscience teams have a wealth of experience and a strong track record of delivery in anti-infective drug discovery. Utilising our combined knowledge, we have demonstrated the ability to rapidly develop integrated screening cascades to efficiently and robustly identify and progress tractable small molecule-based inhibitors of numerous virus-encoded functions.
We also apply our expertise in molecular and cellular biology to perform exploratory studies designed to elucidate novel mechanisms of action utilised by new, or existing, inhibitors of microbial replication cycles. Further, in vitro drug combination studies are employed to quantitatively assess pharmacological synergies between novel and standard-of-care agents to identify superior combination strategies that can be built into rational clinical development strategies.
Our highly experienced integrated team of scientists works closely with clients to rapidly identify promising lead compounds, and efficiently progress them through relevant proof-of-concept studies and on towards the clinic. Our teams have broad experience across viral, bacterial, and fungal pathogens with different routes of administration including IV, Oral and topical.
Established anti-viral assays in use at Sygnature include:
- Cytopathic effect (CPE) screens. Test compounds are evaluated for their ability to inhibit virus-induced CPE. Cells are pre-treated with test compounds and infected with the virus of interest. After a virus-specific incubation period, cells are assessed for their viability relative to an untreated virus-only control.
- Neutralisation assays. The virus is incubated with test compounds before suitable cells are infected. We can offer both plaque-reduction neutralisation assays and microneutralisation, a measurement of cell survival similar to CPE assays.
- Progeny-reduction assays. Cells are incubated with test compounds, and infected with the virus of choice. After a virus-specific incubation time, the supernatants are harvested and the virus titre is determined using a method suitable for the selected virus (50% tissue culture infective dose (TCID50), plaque assays, immunoplaques).
- ELISAs. Measurement of cytokine secretion in response to viral infection, and as a measurement of any inflammatory or anti-inflammatory activity of test compounds.
- RT-qPCR. The detection of viruses in cell supernatant as a diagnostic or as a measure of viral replication.
- Mechanism of action studies. Investigation into the effect of viral replication, viral fusion and infectivity as a means of determining the inhibitory mechanism of test compounds.
- Customisable virus production. Use of mammalian cell culture for virus growth and harvesting, with titration performed by plaque assay.
- Microscopy-based anti-viral and anti-bacterial high content screening. The measurement of changes in cellular phenotype following viral or anti-viral infections, as well as in response to the use of test compounds.
To complement the range of anti-viral assays available in-house, we also perform host cell cytotoxicity analysis of the compounds to ensure the efficacy data is meaningful with respect to therapeutic window.