Novel Carbobicyclic Nucleosides for the Treatment of COVID-19

The Chinese University of Hong Kong Background
Currently there is no specific medication for COVID-19. Although remdesivir is viewed as a promising medication and has been used to treat COVID-19 patients, its outcome is difficult to predict due to its lack of previous clinical trials. Remdesivir (GS-5734) is a small molecule carrying the phosphoramidate feature and adenosine analogue that acts as a broad-spectrum antiviral drug. Its antiviral activity against EBOV and MERS-CoV have been studied, yet the efficacy toward SARS-CoV-2 awaits examinations. Nonetheless, existing knowledge about remdesivir indicates that small molecules with the structure featuring a nucleoside analogue could be a potential pool with promising COVID-19 treatment.
Among many viral replication processes, targeting the key enzymes for genome replication (i.e. RdRP) appears to be an especially attractive strategy. This strategy has proven promising, exemplified by the success of HCV drugs that inhibit NS5B (i.e. the HCV RdRP). In SARS-CoV-2, this process is mediated by the SARS-CoV-2 nsp12, together with its cofactors, nsp7 and nsp8, with possible contributions from nsp10 and nsp14. To this end, CUHK researchers have developed three classes of novel carbobicyclic nucleosides, which are expected to exhibit superior pharmacokinetic properties and lower propensity for drug resistance due to their RNA-like conformation and therefore likely to be incorporated by RdRPs compared toribose-based nucleoside analogues.
Technology Overview
CUHK researchers are developing small-molecule inhibitors for treating the SARS-CoV-2 infection / COVID-19 epidemic by using an integrated chemistry, biochemistry, and structural biology approach. The synthetic carbobicyclic compounds potentially exhibit metabolic stability and bioavailability, compared to ribose-based nucleotides. In addition, preliminary studies showed that the novel carbobicyclic compounds potentially inhibit the enzyme nsp12, an RNA-dependent RNA polymerase (RdRP) that is crucial for viral genome replication of SARS-CoV-2. The researchers plan to further validate these preliminary results using biochemical, in vitro and in vivo models (on RdRP inhibition and protection against infection), which will pave the path for future clinical trials. In summary, the novel carbobicyclic compounds could hold potential for effectively tackling the emergence of viral resistance.
Stage of Development
CUHK researchers have synthesised a library of carbobicyclic nucleosides a few years ago. In the past two months since the emergence of COVID-19, they have successfully generated the homology model of SARS-CoV-2 RdRP and obtained highly promising docking results with carbobicyclic nucleosides. They have also scaled up the synthesis of the compounds and expressed SARS-CoV-2 RdRP for in vitro activity assay. At the same time, the researchers are carrying out cellular assay using primary isolates and scaling up the synthesis of the compounds for preclinical studies. They have obtained some promising results to guide further drug design and development.
The researchers have also identified a druggable site of Nsp12 (SARS-CoV-2 RdRP) using a homology model. They have docked the synthetic carbobicyclic compounds and validated their potential antiviral activities by docking remdesivir to the Nsp12-RdRP and used those predicted docking results and reported literature as a guideline.
The carbobicyclic compounds potentially disrupt the machinery of RdRPs and directly prevent the virus from further synthesizing its RNA chain and thereby attenuate viral life cycles. This will eventually lead to the decrease of viral load in the body.

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