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Anti-Infectives

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. 

Antiviral assays

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.

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Fibrotic diseases

Sygnature Discovery’s integrated teams of medicinal chemists, bio scientists, DMPK and translational scientists have developed significant expertise in drug discovery in the fibrosis field, with a particular focus on kidney, liver and lung fibrosis.

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Metabolic diseases

Sygnature’s scientists have extensive experience in the field of metabolic disease, from early medicinal chemistry right through to in vivo testing. The integrated teams at Sygnature Discovery have a track record of delivering validated drug candidates to clients.

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Oncology and Immuno-oncology

We have successfully delivered more than 16 pre-clinical oncology projects, utilising our Integrated Drug Discovery expertise to develop small molecule drug candidates to treat a variety of cancers such as leukaemia, breast and prostate cancer. From initial screening and profiling through to clinically relevant Biomarkers, our DMPK and bioscience group can provide full support for your discovery projects.

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Anti-Infectives

Sygnature have a history of enabling discovery success in the field of anti-infectives. Our Integrated Drug Discovery teams have worked in close collaboration with many clients to design potent and efficacious compounds. Our Bioscience team can provide cytopathic effect and viability screening assays to assess compounds designed to inhibit virus attachment, entry or replication in human host cells.

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Neuroscience

Our scientists have a well-developed understanding of the challenges associated with the design and optimisation of compounds that target the central nervous system (CNS). Our experience is both broad, reaching across a number of neurodegenerative diseases (such as Alzheimer’s, Parkinson’s and Amyotrophic Lateral Sclerosis) and neuropathic pain, and deep-rooted, with members of our senior team having 10+ years in CNS drug research.

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Respiratory

We have an excellent track record of success in the field of respiratory diseases using our extensive in-house expertise, accelerating 5 compounds to the clinic and a further 4 into preclinical development for our clients. Our collaborative approach to drug discovery and our established network of KOLs in the field have been invaluable to the progression of our clients’ projects

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Inflammation and Immunology

Our scientists have a rich heritage in this therapeutic area and provide significant experience in developing in vitro assays utilising Peripheral Blood Mononuclear Cells (PBMCs), T lymphocytes (e.g. CD4+/CD8+), leukocytes, and phagocytes, amongst others, that assess various inflammation and immunological biomarkers, processes, and endpoints.

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