RNA Synthesis Inhibitors for the Treatment of SARS-CoV-2

The SARS-CoV-2 is a new emerging coronavirus that has not been previously identified in humans. Outbreak of this novel coronaviruses infections among people has raised widespread attention. Treatment with RNA polymerase inhibitors is one way to help stop the virus from replicating and control the infection. Creative Biolabs provides RNA polymerase inhibitors development services for the treatment of SARS-CoV-2. Our staff has decades of experience in anti-coronaviruses drug discovery, providing high-quality, efficient and cost-effective services.

RNA Synthesis in Coronaviruses

Coronaviruses are enveloped, positive-strand RNA viruses with genomes approximately 30 kb in length. The 5’-proximal two-thirds of the genome encodes the replicase gene, which contains two open reading frames, ORF1a and ORF1b. Translation of ORF1a yields polyprotein 1a (pp1a), and −1 ribosomal frameshifting allows translation of ORF1b to yield pp1ab. Together, these polyproteins are co- and post-translationally processed into 16 nonstructural proteins (nsps), most of them driving viral genome replication and subgenomic mRNA (sgmRNA) synthesis. The key enzymes involved in coronavirus RNA synthesis are the RdRp (nsp12), the helicase (nsp13), and the nsp7-nsp8 complex. Given their crucial function in the viral replicative cycle, they are key targets for antiviral research.

Coronavirus genome structure and gene expression. Fig.1 Coronavirus genome structure and gene expression. (Sola, 2015)

  • Nsp12

The RdRp domain, located in the C-terminal region of nsp12, contains all conserved motifs of canonical RdRps. Additionally, nsp12 also contains an N-terminal domain that is essential for RdRp activity and probably interacts with nsp5, nsp8, and nsp9. In vitro, full-length nsp12 drives RNA synthesis in a primer-dependent manner on both homo- and heteropolymeric RNA templates.

  • Nsp7-Nsp8 Complex

Coronavirus nsp8 bears a second, noncanonical RdRp activity that synthesizes short oligonucleotides (<6 nt), acting as an RNA primase that produces the primers required for nsp12-mediated RNA synthesis. Structural studies have indicated that nsp8 interacts with nsp7, forming a hexadecameric protein complex. This complex is active in both de novo initiation and primer extension. The nsp7-nsp8-nsp12 complex formed in vitro is able to catalyze de novo synthesis of relatively long RNAs (up to 340 nt) in a processive manner.

  • Nsp13

Coronavirus nsp13 contains a superfamily 1 helicase domain linked to an N-terminal zinc-binding domain that is essential for helicase activity in vitro. The protein is able to unwind dsRNA and dsDNA in a 5'-to-3’ direction with the energy obtained by the hydrolysis of all NTPs and dNTPs. SARS-CoV nsp13 has been shown to interact specifically with the cellular RNA helicase DDX5, which is involved in coronavirus RNA synthesis.

Polymerase-based Anti-SARS-CoV-2 Treatment Options

All of the mentioned polymerase enzymes of coronavirus that are involved in viral replication are potentially druggable targets. Creative Biolabs provides the following strategies to develop anti-SARS-CoV-2 drugs.

Virus-based and host-based treatment options targeting the coronavirus replication cycle. Fig.2 Virus-based and host-based treatment options targeting the coronavirus replication cycle. (Zumla, 2016)

Our highly trained personnel and investment in state-of-the-art facilities emphasize our commitment to delivering positive customer experiences across all channels of our business. Creative Biolabs is dedicated to providing not only the best in RNA polymerase inhibitors development services, but also the most reliable. We are well-equipped to handle almost any project regardless of scope or complexity. Contact us for more information about RNA polymerase inhibitors drug for the treatment of SARS-CoV-2.

References

  1. Sola, I.; et al. Continuous and discontinuous RNA synthesis in coronaviruses. Annual review of virology. 2015, 2: 265-288.
  2. Zumla, A.; et al. Coronaviruses-drug discovery and therapeutic options. Nature reviews Drug discovery. 2016, 15(5): 327.
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