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

TABLE 1.

Blocking virus‐cell membrane fusion and entry

Drug name and structure 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

Ramipril

graphic file with name DDR-83-16-g125.jpg

ACE inhibitor Type 2 diabetes, vascular disease, hypertension, metabolic syndrome X, peripheral arterial disease, kidney transplant ACE inhibitor NCT04366050 (Phase 2) Phase 2/NCT04366050/enrolling by invitation/May Huaier Granule 11, 2020–May 2021 (Amat‐Santos et al., 2020)

Atovaquone

graphic file with name DDR-83-16-g094.jpg

Mitochondrial cytochrome bc1 complex inhibitor, antimalarial agent HIV infections, malaria, plasmodium falciparum malaria, rabies Elevating endosomal pH and interfere with ACE2 glycosylation

NCT04339426 (Phase 2)

NCT04456153 (Phase 2)

 Phase 2/NCT04456153/completed/July 22, 2020–January 31, 2021 (Clinical trial ID: NCT04456153, n.d.; Farag et al., 2020; Sachdeva et al., 2020)

Enzalutamide

graphic file with name DDR-83-16-g118.jpg

Androgen receptor (AR) antagonist Prostate cancer Blocking TMPRSS2

NCT04456049 (Phase 2)

NCT04475601 (Phase 2)

 Phase 2/NCT04475601/recruiting/July 15, 2020–July 8, 2021 (Cattrini et al., 2020)

Maraviroc

graphic file with name DDR-83-16-g034.jpg

CCR5 antagonist HIV infection, endothelial dysfunction, Inhibiting s‐protein mediated cell fusion and SARS‐CoV‐2 multiplication

NCT04441385 (Phase 2)

NCT04475991 (Phase 2)

NCT04710199 (Phase 2)

NCT04435522 (Phase 1)

 Phase 2/NCT04441385/recruiting/June 26, 2020–November 30, 2020

(Koenig et al., 2020; Risner et al., 2020; Shamsi et al., 2020)

Losartan

graphic file with name DDR-83-16-g065.jpg

AT II receptor antagonist Hypertension, kidney disease, proteinuria, emphysema, colitis, etc. ACE2 blocker preventing virus entry into the host cells

Approximately 8 clinical trials, some of the examples are:

NCT04335123 (Phase 1)

NCT04447235 (Phase 2)

NCT04428268 (Phase 2)

NCT04643691 (Phase 2)

NCT04311177 (Phase 2)

NCT04312009 (Phase 2)

NCT04606563 (Phase 3)

NCT04343001 (Phase 3)

 Phase3/NCT04606563/recruiting/October 9, 2020–June 30, 2021

(Gurwitz, 2020; Messerli et al., 2020)

Isotretinoin (13‐cis‐retinoic acid)

graphic file with name DDR-83-16-g088.jpg

Anti‐apoptosis Severe acne Down‐regulates ACE2 receptors, combination with all‐trans retinoic acid may enhances neutralizing antibodies in COVID‐19 infected Patients

Approximately 9 clinical trials, some of the examples are:

NCT04353180 (Phase 3)

NCT04396067 (Phase 2)

NCT04577378 (Phase 2)

NCT04389580 (Phase 2)

NCT04578236 (Phase 2)

NCT04361422 (Phase 3)

NCT04382950 (Phase 1)

 Phase 3/NCT04353180/not yet recruiting/October 2020–June 2021

(Hamouda Elgarhy, 2020)

Lactoferrin (protein)

 Anti‐microbial, anti‐inflammatory, and immunomodulatory

Anti‐gram‐negative, anti‐gram‐positive bacteria, fungi and viruses

Inhibiting the union of ACE2 with SARS‐CoV‐2 spike protein,

blocking the heparan sulfate proteoglycan receptor

NCT04526821 (Phase 2)

NCT04421534 (Phase 3)

NCT04412395 (Phase 3)

NCT04427865 (Phase 3)

NCT04847791(not applicable)

NCT04475120 (Phase 3)

NCT04713735 (not applicable)

 Phase 3/NCT04475120/completed/April 15, 2020–July 2, 2020

(Chang et al., 2020; Hu et al., 2021)

Propranolol

graphic file with name DDR-83-16-g069.jpg

Non‐selective

β1/β2‐blocker

 Hyperalgesia, social anxiety disorder, migraine headache, cigarette smoking, asthma, etc. Blocking entry of SARS‐COV‐2 through downregulation of the ACE2 receptor and CD147 NCT04467086 (Phase 3) Phase 3/NCT04467086/not yet recruiting/December 2020–April 2021

(Vasanthakumar, 2020)

Linagliptin

graphic file with name DDR-83-16-g124.jpg

DPP‐4 inhibitor Diabetes mellitus, type 2 Inhibiting DPP4, blocking DPP4 inteacting with spike protein of the MERS‐Co‐V NCT04371978 (Phase 3) Phase 3/NCT04371978/recruiting/October 1, 2020–June 30, 2021

(Solerte et al., 2020)

Verapamil

graphic file with name DDR-83-16-g031.jpg

Calcium channel blocker and P‐gp inhibitor, CYP3A4 inhibitor Heart arrhythmias, high blood pressure and angina research

A slow‐channel calcium‐blocking agent.

Blocking ion channels to inhibit coronavirus entry.

NCT04351763 (Phase 3)

 Phase 3/NCT04351763/recruiting/April 27, 2020–March 2, 2021

(Clinical trial ID: NCT04351763, n.d.)

Chlorpromazine

graphic file with name DDR-83-16-g066.jpg

Antagonist of dopamine D2, 5‐HT2A, potassium channel and sodium channel. Psychotic disorders such as schizophrenia. Glioblastoma multiforme K+/Na+ channel inhibitor, inhibits clathrin‐mediated endocytosis,

NCT04366739 (Phase 3)

NCT04354805 (Phase 3)

 Phase 3/NCT04366739/not yet recruiting/April 29, 2020–August 30, 2020

(Plaze et al., 2020)

Dapagliflozin

graphic file with name DDR-83-16-g035.jpg

Competitive SGLT2 inhibitor Diabetes mellitus (DM) Reducing the viral load and preventing the lowering of cytosolic pH NCT04350593 (Phase 3) Phase 3/NCT04350593/active, not recruiting/April 22, 2020–April 2021

(Cure & Cumhur Cure, 2020)

Nafamostat

graphic file with name DDR-83-16-g068.jpg

Serine protease inhibitor, Acute kidney injury TMPRSS2 inhibitor

NCT04390594 (Phase 3)

NCT04352400 (Phase 3)

NCT04418128 (Phase 3)

 Phase 3/NCT04390594/recruiting/August 13, 2020–February 12, 2021

(Fernandez‐Fernandez et al., 2020)

Bicalutamide

graphic file with name DDR-83-16-g087.jpg

Non‐steroidal AR antagonist Prostate cancer, neoplasms, prostate, Blocking TMPRSS2

NCT04509999 (Phase 3)

NCT04652765 (Phase 1)

 Phase 3/NCT04509999/recruiting/October 26, 2020–September 2022

(Cattrini et al., 2020)

Bromhexine

graphic file with name DDR-83-16-g126.jpg

Clearing mucus from respiratory tract, antioxidant Chronic bronchitis, asthma and other causes of phlegm not easy to cough out TMPRSS2 inhibitor

NCT04340349 (Early Phase1)

NCT04424134 (Phase 3)

NCT04355026 (Phase 4)

NCT04273763 (not applicable)

 Phase 4/NCT04355026/recruiting/April 10, 2020–June 30, 2020

(Habtemariam et al., 2020; Maggio & Corsini, 2020)

Camostat

graphic file with name DDR-83-16-g030.jpg

Serine protease inhibitor, Corona virus infection, COVID‐19, coagulopathy cardiovascular complication COVID‐19 TMPRSS2 inhibitor

Approximately 19clinical trials, some of the examples are:

NCT04353284 (Phase 2)

NCT04524663 (Phase 2)

NCT04583592 (Phase 2)

NCT04608266 (Phase 3)

NCT04455815 (Phase 3)

NCT04657497 (Phase 3)

NCT04530617 (Phase 2)

 Phase 4/NCT04338906/withdrawn (lack of public funding)/June 1, 2020–December 2021

(Huang et al., 2020)

Spironolactone

graphic file with name DDR-83-16-g117.jpg

AR antagonist Heart failure, cardiomyopathy, alcoholic, alcoholism, osteoarthritis, Hypoglycemia, healthy Inhibiting the androgen‐dependent expression of TMPRSS2

NCT04643691 (Phase 2)

NCT04424134 (Phase 3)

NCT04826822 (Phase 3)

NCT04345887 (Phase 4)

 Phase 4/NCT04345887/not yet recruiting/April 21, 2020–July 21, 2020

(Cadegiani et al., 2020; Liaudet & Szabo, 2020)

Valsartan (diovan)

graphic file with name DDR-83-16-g093.jpg

AT II receptor antagonist Hypertension stage 2 systolic hypertension

ACE2 inhibitor, inhibition of TMPRSS2

 NCT04335786 (Phase 4) Phase 4/NCT04335786/recruiting/April 17, 2020–December 2020

(Vitiello et al., 2020)

Arbidol (umifenovir)

graphic file with name DDR-83-16-g038.jpg

Antiviral agent Influenza

Inhibition of ACE2/S protein interaction, blocking membrane fusion

NCT04350684 (Phase 4)

NCT04260594 (Phase 4)

NCT04476719 (Phase 1)

 Phase 4/NCT04350684/enrolling by invitation/April 15, 2020–April 22, 2020

(Clinical trial ID: NCT04260594, n.d.; Clinical trial ID: NCT04252885, n.d.; Huang et al., 2020)

Proxalutamide (GT0918)

graphic file with name DDR-83-16-g062.jpg

Androgen receptor (AR) antagonist COVID‐19, Prostate cancer

ACE2 and TMPRSS2 levels in

lung and cardiac cells are reduced by ant androgens

NCT04853134 (Phase 3)

NCT04728802 (Phase 3)

NCT04853927 (Phase 3)

NCT05009732 (Phase 3)

NCT04870606 (Phase 3)

NCT04446429 (not applicable)

 Phase 3/NCT04728802/completed/January 28, 2021–April 15, 2021 (McCoy et al., 2021)

Canrenoate potassium

graphic file with name DDR-83-16-g120.jpg

Competitive mineralocorticoid receptor (aldosterone receptor) antagonist Brain‐dead organ donors, Cirrhosis, COVID‐19 pneumonia

Pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2

expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action

NCT04977960 (Phase 2)

NCT04912011 (Phase 4)

 Phase 4/NCT04912011/recruiting/June 3, 2021–August 31, 2021 (Kotfis & Lechowicz, 2021:)

Defibrotide

graphic file with name DDR-83-16-g090.jpg

Thrombotic microangiopathies, Kawasaki disease, Sickle cell disease Coagulopathy Mediated by the p38 MAPK pathway, which is upregulated as a result of the binding of SARSCoV2 on ACE2 receptors on the surface of endothelial cells and, in turn, activates the transcription of the proinflammatory cytokines.

NCT04335201 (Phase 2)

NCT04652115 (Phase 2)

NCT04530604 (Ohase 1)

NCT04348383 (Phase 2)

 Phase 2/NCT04335201/recruiting/April 6, 2020–June 20, 2021

(Macciò et al., 2020)

Azithromycin

graphic file with name DDR-83-16-g123.jpg

Inhibit translation via interacting with 50S subunit of the bacterial ribosome Acute bacterial, community‐acquired pneumonia, uncomplicated skin infections, et al

Inhibiting viral invasion via interact with spike protein/CD147 interaction or blocking CD147 expression

Approximately 52 clinical trials, some of the examples are:

NCT04334382 (Phase 3)

NCT04371406 (Phase 3)

NCT04359316 (Phase 4)

NCT04339816 (Phase 3)

NCT04332107 (Phase 3)

NCT04621461 (Phase 4)

NCT03871491 (Phase 3)

 Phase 4/NCT04621461/completed/November 2020–February 8, 2021

(Damle et al., 2020; Ulrich & Pillat, 2020)

Tetrandrine

graphic file with name DDR-83-16-g033.jpg

Voltage‐gated Ca2+ current (ICa) and Ca2+‐activated K+ current inhibitor Corona virus disease 2019, COVID‐19 Inhibiting voltage‐gated Ca2+ current (ICa) and Ca2+‐activated K+ current. NCT04308317 (Phase 4) Phase 4/NCT04308317/enrolling by invitation/March 5, 2020–March 1, 2021

(Clinical trial ID: NCT04308317, n.d.; Heister & Poston, 2020)

Doxycycline

graphic file with name DDR-83-16-g070.jpg

Broad‐spectrum metalloproteinase (MMP) inhibitor Anal chlamydia infection, rosacea, overactive bladder, HIV infections, sinusitis, acne vulgaris Inhibition of the E2 envelope glycoprotein involved in virus entry

Approximately 10 clinical trials, some of the examples are:

NCT04591600 (Phase 2)

NCT04523831 (Phase 3)

NCT04371952 (Phase 3)

NCT04370782 (Phase 4)

NCT04407130 (Phase 2)

NCT04551755 (Phase 2)

NCT04584567 (Phase 3)

 Phase 4/NCT04370782/completed/28, 2020–September 30, 2020

(Francini et al., 2020; Maurya, 2020)

Povidone‐iodine

graphic file with name DDR-83-16-g085.jpg

Antibacterial agent (MRSA and MSSA strains) External uses‐infection; cesarean section, vaginal surgeries, arrhythmia

Interacting with surface proteins of enveloped viruses, destabilize membrane fatty acids, inducing cell apoptosis

Approximately 12clinical trials, some of the examples are:

NCT04410159 (Phase 2)

NCT04549376 (Phase 2)

NCT04510402 (Phase 2)

NCT04371965 (Phase 2)

NCT04872686 (Phase 3)

NCT04344236 (Phase 2)

NCT04603794 (Phase 4)

 Phase 4/NCT04603794/recruiting/October 1, 2020–November 2020

(Pattanshetty et al., 2021)