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Anti-monkeypox Drug Discovery Services Targeting Viral Nucleic Acid
In response to the growing monkeypox crisis and the urgent need for anti-monkeypox drug research, Creative Biolabs provides the most comprehensive, reliable and robust one-stop solution for anti-monkeypox drug discovery targeting viral nucleic acid.
Background of Monkeypox Virus
Monkeypox is a systemic disease caused by the monkeypox virus (MPXV) with a fatality rate between 1-10%. Monkeypox virus (MPXV) shares significant homology and structural similarity with other orthopoxviruses. MPXV is a large, enveloped, brick-shaped DNA virus that can only produce and replicate itself within a host cell. MPXV contains approximately 200 kb double-stranded DNA genome, the ends of which are linked by covalent bonds. Upon entry into host cells via pinocytosis or membrane fusion, MPXV releases various viral enzymes and regulatory proteins and undergoes early, intermediate and late gene expression according to a temporal gradient. Replication of viral DNA is complete within 6 hours after infection and produces nearly 100,000 new copies.
There are currently no approved anti-monkeypox drugs, but drugs targeting viral nucleic acid and replication/transcription processes have been studied in various models. Several types of acyclic nucleoside drugs with broad-spectrum anti-DNA virus capacity can selectively inhibit the synthesis of viral DNA mediated by intracellular orthopoxvirus DNA polymerase, thereby effectively controlling the colony of viruses. At the same time, some anthracycline derivatives can inhibit the function of topoisomerase II, resulting in impaired cellular DNA and RNA synthesis and hindering virion assembly. In addition, nigericin also inhibits early gene transcription and translation in orthopoxviruses and severely impairs intermediate and late gene expression. As an inhibitor of viral DNA replication, cytarabine can block the production of viral progeny but does not affect early gene expression.
Fig 1. Nigericin suppresses DNA replication and intermediate/late translation. (Myskiw, 2010)
Drug development of poxvirus is a complex and dangerous process. With the development of virology, molecular biology and pharmacokinetic tools, more and more technical approaches and theories are used in the process of drug discovery.
Drug Screening and Synthesis
Screening, synthesis and preparation of derivatives and antiviral compounds of specific molecular structures are often the basis for drug development.
Plaque Reduction Neutralizing Assay
During monolayer cell culture, if the multiplicity of infection (MOI) is low enough, orthopoxvirus will form distinct plaques within 24-72 hours, and as the MOI index approaches 1, the infection process will destroy the entire cell monolayer within 72 hours. Comparing drug-treated virus with untreated virus, an estimate of the cytopathic effect can be obtained, and the mean effective concentration (EC50) or inhibitory concentration (IC50) of the drug's antiviral efficacy can be estimated.
Virus Entry and Spread Testing
The virulence and infectivity of the virus can be assessed by labeling the virus with luciferase and measuring the number of viruses entering the cell, the number of diffused viruses and the total number of viruses.
Whole Genome Sequencing and Quantitative Real-time PCR
Various conditions may lead to changes in viral gene expression and replication, which may cause adaptive or drug-resistant mutations. Therefore, reporting changes in DNA or RNA and expression status could further enhance current therapeutic development strategies or get a better understanding of MPXV resistance.
Fig 2. Human monkeypox clinical and virological timeline measured by PCR. (Adler, 2022)
In vitro experiments often use monolayer cell experiments, available cell lines include BSC-40, BSC-1, etc. In vivo experiments were performed in animal models including STAT1-deficient immunodeficient mice, ground squirrels, woodchucks or primates.
Some commonly used experimental methods can also be used in the development process of anti-monkeypox drugs, such as enzyme activity detection, enzyme-linked immunosorbent assay, histological section, pharmacokinetic assay, MV/EV quantification and many other approaches. A comprehensive and reliable analysis of MPXV gene expression, protein synthesis, or the pathological conditions caused by it can be performed through these classical biological assays.
With years of experience in the biological field and our outstanding R&D team, Creative Biolabs provides the most comprehensive and reliable one-stop anti-monkeypox drug discovery services targeting viral nucleic acid solutions for clients around the world, not limited to the discovery and early characterization, activity spectrum selectivity, cytotoxicity, and molecular target/mechanism of action assay, non-clinical animal efficacy studies, drug-drug interactions assay. We are the best partner for your monkeypox drug discovery projects, so please contact us and discuss your needs, for us to deliver an appealing proposal.
Myskiw, C.; et al. Nigericin is a potent inhibitor of the early stage of vaccinia virus replication. Antiviral Research. 2010, 88: 304-310.
Adler, H.; et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 2022, 22: 228.