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. 2021 Nov 11;83(1):16–54. doi: 10.1002/ddr.21895

TABLE 2.

Inhibiting virus replication

Drug Original mechanism FDA‐approved indication(s) Possible mechanism for anti‐COVID‐19 Clinical trials ID (stage) The highest anti‐COVID‐19 phase/ID/status/start–(estimated)end dates References

Galidesivir

graphic file with name DDR-83-16-g064.jpg

Viral RNA‐dependent RNA polymerase (RdRP) inhibitor Not yet approved Inhibiting RNA dependent RNA polymerase NCT03891420 (Phase 1) Phase 1/NCT03891420/recruiting/April 9, 2020–May 31, 2021

(Elfiky, 2020; Silva Arouche et al., 2020)

Ebselen (PZ‐51, SPI‐1005, CCG‐39161,)

graphic file with name DDR-83-16-g037.jpg

Potent voltage‐dependent calcium channel (VDCC) blocker Not yet approved Inhibiting main protease via binding to Mpro from forming selenosulfide

NCT04484025 (Phase 2) NCT04483973 (Phase 2)

Phase 2/NCT04484025/not yet recruiting/

May 2021–June 2022

(Haritha et al., 2020; Ma et al., 2020)

Disulfiram (tetraethylthiuram disulfide; TETD)

graphic file with name DDR-83-16-g092.jpg

Aldehyde‐dehydrogenase (ALDH1) inhibitor Cocaine addictive, chronic alcoholism

Blocking the Mpro protease, inhibiting cytokine release induced by NF‐kB and NLRP inflammasome

 NCT04485130 (Phase 2) NCT04594343 (Phase 2) Phase 2/NCT04594343/recruiting/November 20, 2020 –July 20, 2021

(Ma et al., 2020; Wang et al., 2003)

Tafenoquine

graphic file with name DDR-83-16-g119.jpg

Anti‐malarial prophylactic agent. Not yet approved Inhibiting virus infection via down regulating Mpro activity NCT04533347 (Phase 2) Phase 2/NCT04533347/recruiting/February 19, 2021–June 8, 2021

(Chen, Yang, et al., 2020; Dow et al., 2020)

EIDD‐2801 (Molnupiravir, MK‐4482)

graphic file with name DDR-83-16-g086.jpg

Virus RNA mutation Antivirus, not yet approved Induced RNA mutagenesis by the viral RNA‐dependent RNA polymerase (RdRp) NCT04405739 (Phase 2) NCT04392219 (Phase 1) NCT04575584 (Phase 3) NCT04405570 (Phase 2) Phase 3/NCT04575584/active, not recruiting/October 5, 2020–August 10, 2021 (Sheahan, Sims, Zhou, et al., 2020; PubChem, National Library of Medicine, n.d.; Kabinger & Stiller, 2021)

Merimepodib(MMPD, VX‐497)

graphic file with name DDR-83-16-g071.jpg

Noncompetitive inosine monophosphate dehydrogenase (IMPDH) inhibitor Not yet approved Inhibiting Zika viral RNA replication NCT04410354 (Phase 2) Phase 2/NCT04410354/terminated (Failure to meet primary endpoint)/June 16, 2020–December 1, 2020

(X. Tong et al., 2018)

Clevudine (L‐FMAU)

graphic file with name DDR-83-16-g036.jpg

Nucleoside analog of the unnatural L‐configuration, non‐competitive inhibitor that is not incorporated into the viral DNA but rather binds to the polymerase. Chronic hepatitis B Inhibition of viral RNA synthesis

NCT04891302 (Phase 2)

NCT04347915 (Phase 2)

 Phase 2/NCT04347915/recruiting/April 15, 2020–January 30, 2021 (Hui & Lau, 2005; Jang et al., 2011)

Selinexor

graphic file with name DDR-83-16-g063.jpg

Selective nuclear transport (SINE) inhibitor Multiple myeloma Interference nuclear export of vRNPs, viral mRNAs mediated by XPO1, blocking late‐stage viral assembly processes NCT04349098(Phase 2) NCT04355676(Phase 2) Phase 2/NCT04349098/completed/April 17, 2020–October 5, 2020

(Uddin et al., 2020)

Emtricitabine

graphic file with name DDR-83-16-g091.jpg

Nucleoside reverse transcriptase inhibitor (NRTI). HIV infection, PrEP adherence monitoring, healthy, hepatitis B Reverse transcriptase inhibitor

NCT04712357 (not applicable)

NCT04519125 (Phase 2)

NCT04334928 (Phase 3)

NCT04405271 (Phase 3)

 Phase 3/NCT04405271/recruiting/July 31, 2020–April 1, 2021

(Ayerdi et al., 2020)

Tenofovir alafenamide

graphic file with name DDR-83-16-g121.jpg

HIV‐1 nucleotide reverse transcriptase inhibitor HIV infections, hepatitis B. Reverse transcriptase inhibitor

NCT04519125 (Phase

NCT04334928 (Phase 3)

NCT04405271 (Phase 3)

 Phase 3/NCT04405271/not yet recruiting/July 31, 2020–November 15, 2020

(Duan et al., 2020)

Remdesivir

graphic file with name DDR-83-16-g032.jpg

Nucleoside analog with effective antiviral activity Not yet approved

Viral RNA‐dependent RNA polymerase (RdRP) inhibitor, reducing viral multiplication

Approximately 33

clinical trials, some of the examples are:

NCT04539262 (Phase 2)

NCT04610541 (Phase 3)

NCT04501952 (Phase 3)

NCT04292730 (Phase 3)

NCT04560231 (Phase 1)

NCT04672564 (Phase 3)

NCT04480333 (Phase 1)

 Phase3/NCT04292899/completed/March 6, 2020–April 9, 2020

(Coomes & Haghbayan, 2020; Wang, Cao, et al., 2020)

Ciclesonide

graphic file with name DDR-83-16-g122.jpg

Glucocorticoid receptor inhibitor Obstructive airway diseases. Asthma, Allergic Rhinitis, Perennial Inhibiting the replication of SARS‐CoV‐2 genomic RNA via targeting viral endonuclease NSP15

NCT04330586 (Phase 2)

NCT04435795 (Phase 3)

NCT04377711 (Phase 3)

NCT04381364 (Phase 2)

NCT04356495 (Phase 3)

 Phase 3/NCT04377711/completed/June 8, 2020–January 5, 2021

(Kimura et al., 2020)

Ribavirin

graphic file with name DDR-83-16-g067.jpg

Nucleoside inhibitor HIV infections, hepatitis C RNA‐dependent RNA polymerase inhibitor

Approximately 8 clinical trials, some of the examples are:

NCT04828564(Phase 3)

NCT04563208 (Phase 2)

NCT04494399 (Phase 2)

NCT04460443 (Phase 3)

NCT04356677 (Phase 1)

NCT04392427 (Phase 3)

 Phase 3/NCT04392427/not yet recruiting/October 2020–May 2022

(S. Tong et al., 2020; Khalili et al., 2020)

Dipyridamole

graphic file with name DDR-83-16-g089.jpg

Phosphodiesterase inhibitor Cirrhosis, hypertension, status; splenectomy, venous thrombosis, brain ischemia, transient ischemic attack, arteriosclerosis, Suppressing HCoV‐19 replication

NCT04391179 (Phase 2)

NCT04424901 (Phase 2)

NCT04410328 (Phase 3)

 Phase 3/NCT04410328/recruiting/October 21, 2020–March 15, 2021

(Liu, Li, Liu, Chen, & Luo, 2020; Liu, Zheng, Huang, Shan, & Huang, 2020; Ma & Wang, 2021)

Ivermectin

graphic file with name DDR-83-16-g083.jpg

Anti‐parasite agent, impα/β1‐mediated nuclear import inhibitor Healthy, rosacea, lymphatic filariasis, loiasis

Blocking α/β1‐mediated nuclear import

Approximately 56 clinical trials, some of the examples are:

NCT04529525 (Phase 3)

NCT04381884 (Phase 2)

NCT04523831 (Phase 3)

NCT04391127 (Phase 3)

NCT04602507 (Phase 2)

NCT04422561 (Phase 3)

NCT04530474 (Phase 3)

 Phase 3/NCT04523831/completed/June 1, 2020–August 22, 2020

(Heidary & Gharebaghi, 2020; Sharun et al., 2020)

Rosuvastatin

graphic file with name DDR-83-16-g001.jpg

HMG‐CoA

reductase enzyme inhibitor, cholesterol level inhibitor, block hERG current

 Dyslipidemias, non‐ST‐elevation acute coronary syndromes, cardiovascular disease, myocardial infarction, hypercholesterolemia Targeting COVID‐19 virus Mpro NCT04472611 (Phase 3) Phase 3/NCT04362137/not yet recruiting/August 1, 2020–August 1, 2021

(Farag et al., 2020)

Isoquercetin (Quercetin 3‐glucoside, IQC‐950AN)

graphic file with name DDR-83-16-g042.jpg

Regulates the expression of nitric oxide synthase 2 (NO2) via modulating the nuclear factor‐κB (NF‐κB) transcription regulation system Cardiovascular disease, chronic kidney disease, Covid19 Mpro inhibitor

NCT04536090 (Phase 2)

NCT04733651 (Phase 2)

NCT04622865 (Phase 2)

 Phase 2/NCT04622865/recruiting/November 10, 2020–June 2021 (Saeedi‐Boroujeni & Mahmoudian‐Sani, 2021)

Ritonavir

graphic file with name DDR-83-16-g058.jpg

HIV type 1aspartate protease inhibitor HIV infection Inhibit the coronaviral 3CLpro protease

Approximately 24 clinical trials, some of the examples are:

NCT04403100 (Phase 3) NCT04321174 (Phase 3) NCT04291729 (Phase 4) NCT04345276 (Phase 4) NCT04261270 (Phase 3) NCT04386876 (Phase 1) NCT04466241 (Phase 2)

 Phase 4/NCT04291729/completed/February 17, 2020–March 19, 2020

(Cao et al., 2020; Chu et al., 2004; Li & De Clercq, 2020; Ma et al., 2021; Sheahan, Sims, Leist, et al., 2020; Zhang, Lin, et al., 2020)

Etoposide (VP‐16; VP‐16‐213)

graphic file with name DDR-83-16-g105.jpg

Topoisomerase II inhibitor Adult acute lymphocytic leukemia, NK + T Cell lymphoma, mantle cell lymphoma, small cell lung cancer SARS‐3CL protease inhibitor NCT04356690 (Phase 2) Phase 2/NCT04356690/Active, not recruiting/April 22, 2020–December 2021 (Rashid et al., 2022)

PF‐07321332

graphic file with name DDR-83-16-g109.jpg

SARS‐CoV 3C‐like protease (3CLPRO) inhibitor COVID‐19 3CLpro inhibitor

NCT04960202 (Phase 3)

NCT04962230 (Phase 1)

NCT05005312 (Phase 1)

NCT04909853 (Phase 1)

NCT04962022 (Phase 1)

NCT05032950 (Phase 1)

NCT04756531 (Phase 1)

NCT05011513 (Phase 3)

 Phase 3/NCT04960202/recruiting/July 13, 2021–October 16, 2021 (Vandyck & Deval, 2021)

PF‐07304814

graphic file with name DDR-83-16-g019.jpg

Potent 3CLpro protease (Mpro) inhibitor Viral disease 3CLpro proteaseinhibitor

NCT04535167 (Phase 1)

NCT04627532 (Phase 1)

 Phase 1/NCT04627532/completed/November 13, 2020–December 17, 2020 (Boras, 2021; Vandyck & Deval, 2021)

Lopinavir

graphic file with name DDR-83-16-g015.jpg

HIV type 1 aspartate protease inhibitor HIV infection

Inhibit the viral proteases: 3CLpro or Plpro, increasing t1/2 via inhibiting cytochrome P450 when combined with lopinavir

Approximately 18

clinical trials, some of the examples are:

NCT04403100 (Phase 3)

NCT04307693 (Phase 2)

NCT04321174 (Phase 3)

NCT04455958 (Phase 2)

NCT04255017 (Phase 4)

NCT04330690 (Phase 2)

NCT04386876 (Phase 1)

 Phase 4/NCT04255017/recruiting/February 1, 2020–June 1, 2020

(Cao et al., 2020; Chu et al., 2004; Li & De Clercq, 2020; Ma et al., 2021; Sheahan, Sims, Leist, et al., 2020; Zhang, Lin, et al., 2020)

Oseltamivir

graphic file with name DDR-83-16-g007.jpg

Virus neuraminidase enzyme inhibitor Influenza A and B viruses Virus‐release blockers NCT04303299 (Phase 3) NCT04558463 (Phase 3) NCT04516915 (Phase 3) NCT04255017 (Phase 4) NCT02735707 (Phase 4) NCT04338698 (Phase 3) Phase 4/NCT04255017/recruiting/February 1, 2020–June 1, 2020

(Akram et al., 2020; Clinical trial ID: NCT04255017, n.d.; Whitley, 2007)

Favipiravir

graphic file with name DDR-83-16-g075.jpg

Viral RNA polymerase inhibitor Influenza

RNA dependent RNA polymerase inhibitor, reducing virus replication

Approximately 38 clinical trials, some of the examples are:

NCT04402203 (Phase 3) NCT04464408 (Phase 3) NCT04359615 (Phase 4) NCT04303299 (Phase 3) NCT04529499 (Phase 3) NCT04349241 (Phase 3) NCT04600999 (Phase 3) NCT04613271 (Phase 3)

 Phase 4/NCT04359615/not yet recruiting/April 20, 2020–May 3, 2020

(Coomes & Haghbayan, 2020; Wang, Cao, et al., 2020)

Ledipasvir

graphic file with name DDR-83-16-g106.jpg

Inhibitor of the hepatitis C virus NS5A

 Hepatitis C, hepatocellular carcinoma RdRP inhibitor NCT04498936 (Phase 4) NCT04530422 (Phase 3)

Phase 4/NCT04498936/

sofosbuvir/ledipasvir and nitazoxanide for treatment of COVID‐19

(Mevada et al., 2020; Sayad et al., 2020)

Sofosbuvir

graphic file with name DDR-83-16-g102.jpg

HCV RNA replication inhibitor Hepatitis C, liver cirrhosis RdRP inhibitor

Approximately 8 clinical trials, some of the examples are:

NCT04530422 (Phase 3) NCT04498936 (Phase 4) NCT04497649 (Phase 3) NCT04532931 (Phase 2) NCT04535869 (Phase 3) NCT04561063 (Phase 2) NCT04460443 (Phase 3)

 Phase 4/NCT04498936/completed/July 15, 2020–October 30, 2020

(Ju et al., 2020; Elfiky, 2020; Sayad et al., 2020)

GS‐441524

graphic file with name DDR-83-16-g017.jpg

Inhibits feline infectious peritonitis virus (FIPV), parent nucleoside of remdesivir COVID‐19

Interferes with the SARS‐CoV‐2 RNA‐dependent RNA

polymerase (RdRp)

 NCT04859244 (Phase 1) Phase 1/NCT04859244/completed/April 26, 2021–May 1, 2021 (Yan & Muller, 2020)

AT‐527 (R07496998)

graphic file with name DDR-83-16-g022.jpg

HCV viral replication inhibitor HCV Infection Inhibit the RdRp for RNA synthesis

NCT04889040 (Phase 3)

NCT04709835 (Phase 2)

NCT04396106 (Phase 2)

NCT04877769 (Phase 1)

 Phase 3/NCT04889040/recruiting/May 17, 2021–August 3, 2021 (Good et al., 2021)

Darunavir

graphic file with name DDR-83-16-g073.jpg

HIV protease inhibitor HIV infections, healthy Protease inhibitor

NCT04252274 (Phase 3) NCT04435587 (Phase 4) NCT04303299 (Phase 3)

 Phase 4/NCT04435587/recruiting/July 13, 2020–June 2021

(Kutlu & Metin, 2020; Papic et al., 2020)