Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including the newly emerged coronavirus SARS-CoV-2

Authors: Xiong, R. et al. Link to paper: https://www.biorxiv.org/content/10.1101/2020.03.11.983056v1

Journal/ Pre-Print: bioRxiv

Key Words: De novo pyrimidine synthesis pathway, RNA viruses, broad-spectrum antivirals, drug discovery

RESEARCH HIGHLIGHTS 

1. DHODH, a key enzyme in the de novo pyrimidine synthesis pathway, identified as an attractive target for inhibiting multiple RNA viruses.

2. Description of two new inhibitors of DHODH showing good safety profiles.

3. These new inhibitors and an older FDA-approved inhibitor block replication of Influenza A, Ebola, Zika and SARS-CoV-2 in vitro.

SUMMARY 

RNA viruses replicate using cellular ribonucleotides produced via the de novo pyrimidine synthesis pathway. DHODH, a rate-limiting enzyme in this pathway, is an attractive target for broad-spectrum antivirals. This paper describes two new DHODH inhibitors: S312 and S416. S312, S416 and Teriflunomide, an FDA-approved DHODH inhibitor, show low cytotoxicity and high antiviral efficacy in cells infected with RNA viruses, including Influenza A and SARS-CoV-2. In influenza A-infected mice, S312 exhibited antiviral activities equivalent to anti-Influenza drug, Oseltamivir, in early phases of infection while combination treatment was more efficient in later phases. Authors propose Teriflunomide could be tested for COVID-19 treatment. 

IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS

· Potential new treatment strategy of SARS-CoV2/COVID19 positive individuals

· Proposed new drugs effective against RNA viruses including SARS-CoV-2 in vitro and could be tested in vivo.

STUDY TYPE

· In vitro study

· In vivo study (mouse, but not on SARS-CoV-2)

STRENGTHS AND LIMITATIONS OF THE PAPER

Novelty: Presents a new class of drugs that could be used to target RNA viruses through inhibiting DHODH. Specifically, they identify two novel DHODH inhibitors.

Standing in the field: There are previously discovered and FDA approved drugs that similarly target the de novo pyrimidine biosynthesis pathway. However, this class of drugs has not been tested on SARS-CoV-2.

Appropriate statistics: In vivo studies use low numbers of mice (n=4-5 per condition) thus preventing any statistical analysis. Appropriate statistics were used in the in vitro studies.

Viral model used: Primary Wuhan Coronavirus strain used (Beta CoV/Wuhan/WIV04/2019). In vivo mice work uses Influenza A strains as RNA virus models (A/WSN/33(H1N1), A/Songhu/06(H3N2), A/Guangzhou/99(H9N2)).

Translatability: Promising in vitro work but with no in vivo work on SARS-CoV-2. Significant in vivo work required to be translatable to bedside.

Main limitations:

· In vivo work with flu suggests these inhibitors are not very effective on their own but could be used in combination with other anti-viral drugs.

· The in vivo work uses small groups of mice (as mentioned above).

· Only in vitro/cell culture work carried out against SARS-CoV-2.

· In vivo experiments initially use 3 doses of inhibitors and protection against severe disease does not seem to correlate with the dose used. Moreover, in subsequent experiments they use the maximum dosage which didn’t work as effectively as other doses in the initial experiment.