Clioquinol: To harm or heal

Abstract

Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.

Discovery of Clioquinol and Analogues as Novel Inhibitors of Severe Acute Respiratory Syndrome Coronavirus 2 Infection, ACE2 and ACE2 - Spike Protein InteractionIn Vitro

“…Clioquinol and its derivatives belonging to 8-hydroxyquinoline structural class, have been investigated extensively in basic, translational and clinical studies because of their multiple activities as metal chelators and zinc ionophores, modulating underlying molecular and physiologic switches required for metal homeostatis in vivo [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][36][37][38][39] . Previously, CLQ was used to treat bacterial infections 62 ; however, it was withdrawn from the clinic because of untoward effects of subacute myelo-optic neuropathy (SMON) mostly experienced in Japan in the 1950's 29,62,63 . More recent studies revealed that SMON might be due to other biologic factors and/or pharmacogenetics primarily linked to the Japanese population 29,62,64 .…”

“…Previously, CLQ was used to treat bacterial infections 62 ; however, it was withdrawn from the clinic because of untoward effects of subacute myelo-optic neuropathy (SMON) mostly experienced in Japan in the 1950's 29,62,63 . More recent studies revealed that SMON might be due to other biologic factors and/or pharmacogenetics primarily linked to the Japanese population 29,62,64 . Currently in the clinic, CLQ is approved for use in combination with other agents for treatment of inflammatory skin disorders and fungal infections in some countries 14,65 .…”

“…Currently in the clinic, CLQ is approved for use in combination with other agents for treatment of inflammatory skin disorders and fungal infections in some countries 14,65 . More recently, CLQ and its newer structural derivatives have gained renewed interest as potential drugs for the development of therapeutics for neurodegenerative diseases, cancer, and infectious diseases [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][36][37][38][39] . revealed "a large inhibitor-dependent hinge bending movement of one catalytic subdomain relative to the other that brings important amino acid residues into position for catalysis," similar to observed subdomains on other zinc metalloproteases respectively 48 .…”

“…More recently, CLQ and its analogues have been extensively investigated as potential treatments for cancer and neurodegenerative diseases [21][22][23][24][25][26][27][28] . Additional studies have also shown the involvement of CLQ in the efflux mechanisms of ATP binding cassette (ABC) transporters 29,30 and the cellular autophagic pathway 31,32 , a critical process in the host defense machinery against viral infections 33 . Furthermore, using a high-throughput screen (HTS) and chemical genomics approach, Olaleye, O., et.…”

Targeting zinc metalloenzymes in coronavirus disease 2019

“…Clioquinol was a registered drug worldwide until its use was associated with the occurrence of subacute myelo-optic neuropathy, a condition primarily endemic to Japan. Today, in view of new information that may explain this phenomenon, clioquinol serves as a drug lead to treat cancer (Perez, Sklar, & Chigaev, 2019).…”