Open Access
Review
Table 6
Repositioned drugs and their mechanisms of action.
| Name of the compound | Function | Mechanism of action | References |
|---|---|---|---|
| Anti-fungal | |||
| Miconazole | Anti-fungal | Disruption of sterol synthesis. | [3] |
| Ravuconazole | Invasive fungal infections | Azoles inhibit the sterol biosynthesis pathway by inhibiting the conversion of lanosterol to zymosterol by the monooxygenase lanosterol C14α-demethylase. | [99] |
| Butenafine | Fungal skin infections (ringworm, athlete’s foot, jock itch, pityriasis) | Ergosterol biosynthesis disruption via inhibition of squalene epoxidase. | [10] |
| Anti-bacterial | |||
| Delamanid | Anti-tuberculosis (approved for multidrug resistant strains) | Inhibition of mycobacterial cell wall components synthesis, methoxy mycolic acid and ketomycolic acid. Activation by the enzyme deazaflavin-dependent nitroreductase, leading to a reactive intermediate metabolite that inhibits mycolic acid production. | [74] |
| SQ109 | Resistant mycobacterium tuberculosis (phase IIb/III) | Disruption of intracellular Ca2+ homeostasis, collapsing of the mitochondrial electrochemical potential and affecting acidocalcisomes. | [33] |
| Anti-trypanosomatids | |||
| Fexinidazole | Anti-trypanosomiasis (clinical trial phase II/III in 2019) | Targets nitroreductase in trypanosomatids, which possesses a homolog in Leishmania parasites. | [74] |
| Suramin | Hemolymphatic stage of African trypanosomiasis (Trypanosoma. brucei rhodesiense) | Inhibition of glycolytic enzymes of the parasite. Elevates pro-inflammatory Th1 cytokine secretion while suppressing Th2 responses. | [46] |
| Anti-cancer | |||
| Miransertib (ARQ 092) | PI3K/Akt-driven tumors or Proteus syndrome | Akt inhibitor, activated by Leishmania and regulates cell growth, survival, and metabolism by phosphorylating downstream targets. | [67] |
| AR-12 (OSU-03012) | Anti-cancer (FDA IND-approved) | Host-mediated compound promoting other intracellular pathogen eradication, mediated by regulation of autophagy and Akt kinase pathway inhibition. | [17] |
| Ibrutinib | Anti-cancer for B cell malignancy | ITK/BTK inhibitor, blocking B-cell receptor signaling and proliferation (activated by Leishmania). Modulation of T-helper response. | [104] |
| EAPB0503 (Imiquimod analog) and Imiquimod | Skin cancer and condyloma | TLR-7 agonist leading to NF-kB pathway activation. | [27] |
| Anti-depressants | |||
| Sertraline | Anti-depressant | Serotonin reuptake inhibitor | [52] |
| Clomipramine | Anti-depressant and anxiolytic, treatment of psychiatric disorders and OCD | Selective inhibition of serotonin-reuptake. Previous repurposing studies showed effect on parasites through trypanothione reductase. | [87] |
| Imipramine | Severe chronic depression | Inhibition of serotonin and norepinephrine reuptake. Known interaction with lipid bilayers and inhibition of methyltransferases leading to membrane disruption. | [3] |
| Other | |||
| Simvastatin | Cholesterol reducer | Increase in LDL-cholesterol degradation and HMG-CoA reductase inhibitor. | [72] |
| Rapamycin, GSK-2126458 | Graft rejection prevention Immunosuppressor | mTOR inhibitors. TOR from Leishmania is important in autophagy, and TOR1 and 2 are essential to parasite growth and virulence. | [45] |
| Amiodarone | Antiarrhythmic | Disruption of intracellular Ca2+ homeostasis by direct action on mitochondrion and acidocalcisomes. Blocking of sterol biosynthesis pathway through inhibition of squalene epoxidase activity. | [71] |
ITK/BTK: interleukin 2-inducible T-cell kinase/Bruton tyrosine kinase; HMG-CoA: hydroxymethylglutaryl-CoA reductase; mTRO: mechanistic target of rapamycin; OCD: obsessive-compulsive disorder; TLR: toll-like receptor.
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