TABLE 1.
Candidate anti-SARS-CoV-2 therapeutics based on NPC1 inhibition and NP-C disease mimetic mechanisms
| Generic Name (CAS Number) | Brand Name | Clinical Contraindications/Side Effects | Conventional Use | Drug Mechanism | Antiviral Activity | References |
| NPC1 inhibitors | ||||||
| U18666Aa (3039-71-2) | U18666A | Not applicable | Laboratory use | Inhibits NPC1 | EBOV, IAV, HCV, CHIKV, ZIKV, DENV, WNV, HIV, SARS-CoV-1, MERS-CoV, type I FCoV | (25–28, 46–50, 53) |
| Imipraminea (50-49-7) | Tofranil, Janimine, Melipramine | Mood disorders, nausea, angle-closure glaucoma | Antidepressant | Inhibits NPC1, inhibits TPC2 | EBOV, CHIKV, ZIKV, DENV, WNV | (24, 26, 60, 61) |
| Cepharanthinea (481-49-2) | Cepharantin | Well tolerated | Anti-inflammatory, anticancer | Inhibits NPC1, inhibits TPC2 | HIV, Pangolin coronavirus | (58, 63–66, 117) |
| Itraconazole (84625-61-6) | Onmel, Sporanox, Tolsura | Heart failure, QT prolongation | Antifungal | Inhibits NPC1 | IAV, DENV, PeV-A3, EV, HCV, type I FCoV | (57, 67–73) |
| Posaconazole (171228-49-2) | Noxafil, Posanol | Heart failure, QT prolongation | Antifungal | Inhibits NPC1 | IAV, DENV, ZIKV, YFV, PeV-A3, EV, HCV, type I FCoV | (59, 67, 69–72) |
| NP-C disease mimetics | ||||||
| Chloroquinea,b (54-05-7) | Aralen | Heart failure, QT prolongation | Antimalarial | Lipid accumulation in the LE/L, increases pH | CHIKV, ZIKV, EBOV, HCV, HIV, IAV, EV, SARS-CoV-1, MERS-CoV, SARS-CoV-2 | (74, 80, 81, 83–87, 118) |
| Hydroxychloroquinea,b (118-42-3) | Plaquenil | Heart failure, QT prolongation | Antimalarial | Lipid accumulation in the LE/L, increases pH | HIV, SARS-CoV-1, SARS-CoV-2 | (79, 80, 82) |
| Azithromycin a,b (83905-01-5) | Zithromax, Sumamed | Heart failure, QT prolongation, liver dysfunction | Antibacterial | Lipid accumulation in the LE/L, increases pH | ZIKV, RV | (75, 90, 91) |
| Chlorpromazine hydrochloridea (69-09-0) | Sonazine, Chloractil | Dementia in older patients, mood disorders | Antipsychotic, antidepressant | Lipid accumulation in the LE/L, inhibits clathrin-mediated endocytosis | SARS-CoV-1, MERS-CoV, WNV, IV, HPEV-1, JEV, HPyV-2 | (6, 76, 84, 86, 93–98) |
| Haloperidola (52-86-8) | Haldol, Aloperidin | Dementia in older patients, mood disorders | Antipsychotic, antiemetic | Lipid accumulation in the LE/L | (78) | |
| Amiodaronea (1951-25-3) | Cordarone | Lung, liver damage, arrhythmia | Antiarrhythmic | Lipid accumulation in the LE/L, alters late compartments of the endocytic pathway | SARS-CoV-1, EBOV, HCV | (77, 100–102) |
Approved drugs that inhibit NPC1 or mimic NP-C disease that have previously shown antiviral activity. Drug specifications from https://pubchem.ncbi.nlm.nih.gov/. Contraindications and side effects are from Medline https://medlineplus.gov/drugreactions.html. Parechovirus A3 (PeV-A3); yellow fever virus (YFV); rhinovirus (RV); influenza virus (IV); human parechovirus 1 (HPEV-1); Japanese encephalitis virus (JEV); human polyomavirus 2 (HPyV-2).
a
Cationic amphiphile.
b
Currently in COVID-19 clinical trial.