A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses
Abstract
:1. Introduction
2. The Pyrimidine Synthesis Pathway Is a Reliable HTA Target
3. The Essential Role of DHODH in the De Novo Pyrimidine Synthesis Pathway
4. DHODHi Inhibit the Virus Replication Cycle
5. DHODHi Stimulate the Expression of ISGs
6. DHODHi Inhibit the Production of Inflammatory Cytokines
7. DHODHi Applications in Antiviral Treatment
7.1. Leflunomide and Teriflunomide
7.2. Brequinar
7.3. S312 and S416
7.4. PTC299
7.5. IMU-838
7.6. Compound A3
7.7. FA-613
7.8. BAY2402234
7.9. MEDS433
7.10. RYL-634
8. Conclusions and Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Host Targets | Description of Host Targets | HTAs | Known Antiviral Effects |
---|---|---|---|
DHODH | The rate-limiting enzyme in the de novo pyrimidine synthesis pathway | Leflunomide, teriflunomide, and brequinar | Influenza virus, HBV, HCV, EBOV, DENV, SARS-CoV-2, HIV, and ZIKV |
Chemokine receptors type 5 | A G-protein coupled receptor, which is an HIV-1 co-receptor associated with CXCR4 | Maraviroc, PF-232798, TAK-220, and INCB9471 | HIV |
Inosine monophosphate dehydrogenase | The rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides | Ribavirin, mycophenolic acid, mycophenolate mofetil, and mizoribine | RSV, HCV, HBV, HCMV, EMCV, ZIKV, and EBOV |
Cyclophilins | A peptidyl-prolyl isomerase, catalyzing the isomerization of peptide bonds from trans to cis form at proline residues to facilitate protein folding | Cyclosporin A, NIM811, and alisporivir | HCV |
Eukaryotic initiation factor 2α | A eukaryotic initiation factor required for most eukaryotic translation initiation | Nitazoxanide, tizoxanide, and RM5061 | Influenza virus, HBV, HCV, EBOV, DENV, JEV, HIV, and ZIKV |
Dihydrofolate reductase | An enzyme converting dihydrofolate into tetrahydrofolate for the de novo synthesis of purines, thymidylic acid, and certain amino acids | Methotrexate, trimetrexate, and 1-aryl-4,6-diamino-1,2-dihydrotriazines | ZIKV, influenza virus, and RSV |
α-Glucosidase | An enzyme catalyzing the hydrolysis of glycosidic bonds in complex sugars | NB-DNJ and Celgosivir | HIV, HCV, human coronavirus, influenza A virus, and DENV |
Kinases | An enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates | Sunitinib and erlotinib | DENV and EBOV |
Sodium taurocholate cotransporting polypeptide | A multiple transmembrane transporter involved in the circulation of bile acids, and served as a common receptor of HBV and HDV | Myrcludex B, CsA, ezetimibe, and ritonavir | HBV and HDV |
Farnesoid X receptor | A nuclear bile acid receptor that regulates the expression of bile acid transporters | GW4064, WAY362450, fexaramine, and chenodeoxycholic acid | HBV |
Diacylglycerol acyltransferases | An enzyme catalyzing the terminal step in triacylglycerol synthesis | pradigastat | HCV |
DHODHi | Key Binding Site Residues | Molecular Structure | Antiviral Activities | Clinical Applications |
---|---|---|---|---|
Leflunomide | Tyr356, Met 43, His56, Ala55, Ala59, Pro364, Val134, Gln47, Arg136, Phe98 | | Influenza A virus (H1N1), ZIKV, EBOV, SARS-CoV-2, BK virus, DENV, porcine epidemic diarrhea virus, CMV, RSV, herpes simplex virus type 1, and HCMV | Phase I/II/III (SARS-CoV-2) Phase I (HIV) Phase II (BK virus) |
Teriflunomide | Tyr356, Met 43, His56, Ala55, Ala59, Pro364, Val134, Arg136, Gln47, Phe98 | | SARS-CoV-2, Human T-lymphotropic virus type-1, JUNV, influenza virus (H5N1), EBV, EV71, and HIV | Phase I/II (HTLV-1) |
Brequinar | Arg136, Met 43, Gln47, Leu46, Leu42, His56, Tyr38, Pro326, Tyr356, Pro69, Val143, Val134 | | SARS-CoV-2 flaviviruses, alphavirus, rhabdovirus, influenza viruses, EV71, EV70, and Coxsackievirus B3 | Phase I/II (SARS-CoV-2) |
IMU838 | Arg136, Met 43, Gln47, Leu46, Leu42, His56, Tyr38, Pro326, Tyr356, Pro69, Val143, Val134 | | SARS-CoV-2, HCMV, HIV-1, and HCV | Phase II/III (SARS-CoV-2) |
S416 | Tyr38, Leu42, Met43, Leu46, Gln47, Pro52, Ala55, His56, Ala59, Phe62, Thr63, Leu67, Leu68, Pro69, Phe98, Met111, Val134, Arg136, Val143, Tyr356, Leu359, Thr360 | | Influenza A virus (H1N1, H3N2, H9N2), ZIKV, EBOV, and SARS-CoV-2 | —— |
S312 | Tyr38, Leu42, Met43, Leu46, Gln47, Pro52, Ala55, His56, Ala59, Phe62, Thr63, Leu67, Leu68, Pro69, Phe98, Met111, Val134, Arg136, Val143, Tyr356, Leu359, Thr360 | | Influenza virus (H1N1, H3N2, H9N2), ZIKV, EBOV, and SARS-CoV-2 | —— |
FA-613 | Tyr356, Arg136, Ala55, Ala59, Leu 46, Thr360 | | Influenza A virus (H5N1 and H7N9), EV-A71, RSV, human rhinovirus A, SARS-CoV, and MERS-CoV | —— |
PTC299 | Tyr356, Phe98, Met111, Leu68, Pro364, Phe62, Met43, Leu58, Leu46, Leu50, Ala55, Arg136, His56, Ala59, Gln47, Val134, VAL143, Thr63 | | SARS-CoV-2, HCV, Poliovirus, EBOV, and Rift Valley Fever | —— |
Compound A3 | Tyr356, Arg136, Ala55, Ala59, Leu46, Pro364, Phe336 | | Influenza A virus (A/WSN/33), influenza B virus (B/Yamagata/88), Newcastle disease virus (La Sota), Sendai virus (SV52), Vesicular stomatitis virus, Sindbis virus, HCV, West Nile virus, DENV-1, NYVAC, hAd5, and HIV-1 | —— |
BAY2402234 | Thr63, Tyr38, Leu42, Met43, Leu46, Leu50, Leu58, Ala59, Phe62, Leu67, Leu68, Pro69, Met111, Leu359, Pro364, Thr360 | | SARS-CoV-2 | —— |
MEDS433 | Gln47, Phe62, Arg136, Thr360 | | HCoV-OC43, HCoV-229E, SARS-CoV-2, and HSV | —— |
RYL-634 | Tyr38, Leu42, Leu46, Gln47, Phe62, Leu67, Arg136 | | HCV, DENV, ZIKV, chikungunya virus, EV71, HIV, RSV, severe fever with thrombocytopenia syndrome virus, and influenza virus | —— |
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Zheng, Y.; Li, S.; Song, K.; Ye, J.; Li, W.; Zhong, Y.; Feng, Z.; Liang, S.; Cai, Z.; Xu, K. A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses. Viruses 2022, 14, 928. https://doi.org/10.3390/v14050928
Zheng Y, Li S, Song K, Ye J, Li W, Zhong Y, Feng Z, Liang S, Cai Z, Xu K. A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses. Viruses. 2022; 14(5):928. https://doi.org/10.3390/v14050928
Chicago/Turabian StyleZheng, Yucheng, Shiliang Li, Kun Song, Jiajie Ye, Wenkang Li, Yifan Zhong, Ziyan Feng, Simeng Liang, Zeng Cai, and Ke Xu. 2022. "A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses" Viruses 14, no. 5: 928. https://doi.org/10.3390/v14050928