Adenosine Analogue for the Treatment of SARS-CoV-2

Studies indicated that adenosine analogues revealed high efficacy as RNA polymerase inhibitors. Thus, the therapeutic potential of adenosine analogues and conjugates has been extensively studied in recent years. Creative Biolabs provides chemical synthesis services and specializes in custom synthesis. Specifically, we offer our customers a broad range of adenosine analogues development services, from the first-time synthesis of complex and commercially not available compounds to the optimization of synthetic routes and biophysical characterization, assessment and modeling of the product.

Introduction of Adenosine

Adenosine is a nucleoside signaling molecule that participates in numerous processes in the human body. The main role of adenosine is to maintain homeostasis and its neuromodulatory action. Adenosine acts through the adenosine receptor (AR), A1AR, A2AAR, A2BAR, and A3AR. Besides being the ligand for the ARs, adenosine is involved in key biochemical processes. For instance, RNA requires purine nucleoside substrates for its synthesis. Adenosine is a part of ATP and cAMP. Therefore, adenosine has been an important target molecule for the development of new medicines against numerous diseases. However, the clinical utility of adenosine is restricted due to its short half-life in blood and non-selectivity towards different receptor subtypes. Since receptor selectivity is highly important to minimize side effects and achieve the desired effects, numerous adenosine analogues have been synthesized.

Adenosine structure Fig.1 Adenosine structure. (Samsel, 2011)

Adenosine Analogues Application Examples

  • Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV) infection in cultured cells, mice and nonhuman primate models.
  • Adenosine analogues are a new alternative for treatment of Human African Trypanosomiasis (HAT), by inhibiting S-adenosylmethionine decarboxylase (AdoMetDC), an enzyme taking part in the rate-limiting step of polyamine biosynthesis.
  • The adenosine analogues NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase (RdRp) of the dengue virus (DENV) by terminating its RNA chain synthesis. Since the initial discovery of NITD008, it has also been found to inhibit the replication of other virus including, but not limited to: Zika virus, hepatitis C virus, West Nile virus, and Yellow fever virus.
  • The adenosine analogue BCX4430 shows broad-spectrum antiviral activity against a wide range of RNA viruses, such as West Nile Virus and Tick-Borne Flaviviruses.

Services at Creative Biolabs

At Creative Biolabs, many achievements have been made in developing compounds containing the adenosine moiety that are considered potential drugs. Besides AR agonists with good selectivity and efficacy, binary drugs are achieved by tethering adenosine to a ligand for a different domain or type of receptor. The third noteworthy group is adenosine analogues. For example:

  • In humans, the distribution of A3AR subtype is expressed in the lungs, liver, heart, kidneys and brain. The widespread distribution in different cells and tissues of the A3AR suggests a potential involvement in various pathologies and the possible use as a selective pharmacological target. Creative Biolabs designed and synthesized a series of 2-O-alkyl-substituted adenosine analogues with indole moiety. It was confirmed to be a modulator in a functional assay measuring its capacity in cells expressing the A3AR.
  • N6-substituted adenosine analogues containing cyclic hydrazines or chiral hydroxy (ar)alkyl groups, designed to interact with the S2 and S3 receptor subregions, have been synthesized and their binding to the A1AR and A2AAR have been investigated. Affinity studies of selected analogues to the A1AR and A2AAR were also carried out by Creative Biolabs.
  • Several new 4’-amino substituted carbocyclic adenosine analogues were prepared.

Guanosine served as the starting material in the synthesis of 2-chloro-N6-substituted adenosine analogues Fig.2 Guanosine served as the starting material in the synthesis of 2-chloro-N6-substituted adenosine analogues. (Ha, 1997)

We supply our clients with custom-made adenosine analogues molecules for their SARS-CoV-2 drug research. Our custom drug discovery services including but not limited to:

At Creative Biolabs, teams of experienced organic chemists can produce a variety of adenosine analogues molecules for your drug discovery research. Please feel free to contact us for more information.

References

  1. Samsel, M.; Dzierzbicka, K. Therapeutic potential of adenosine analogues and conjugates. Pharmacological Reports. 2011, 63(3): 601-617.
  2. Ha, S. B.; et al. New base-altered adenosine analogues: synthesis and affinity at adenosine A1 and A2A receptors. Bioorganic & medicinal chemistry letters. 1997, 7(24): 3085-3090.
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