NEWS ｜ 19 July 2024

WIKIMOLE—Chloroquine

 

By TargetMol

 

Chloroquine (CQ) is a commonly used antimalarial drug. In addition to its antimalarial properties, it is also used for anti-inflammatory, antiviral, and antitumor treatments. Its core structure is the 7-chloroquinoline ring.

Mechanism of Action

-Antimalarial Mechanism

1. Specific Mechanism of Chloroquine Concentration in Plasmodium: Plasmodium has a specific mechanism for concentrating chloroquine. After the application of chloroquine, the drug's concentration within the lysosomes of Plasmodium is more than a thousand times higher than that within the lysosomes of the host.

2. Chloroquine Binding to DNA: Chloroquine binds to DNA by the negatively charged 7-chloro group on the quinoline ring approaching the 2-amino group on guanine in the DNA. This allows chloroquine to insert between the two strands of the DNA double helix. The formation of a chloroquine-DNA complex prevents DNA replication and RNA transcription.

3. Increasing pH: Chloroquine is a weakly basic drug that, upon entering Plasmodium cells in large quantities, increases the pH of their cytosol. This creates an environment unfavorable for proteolytic enzymes, reducing the parasite's ability to degrade and utilize hemoglobin, leading to a deficiency in essential amino acids. Additionally, the increased pH can inhibit the fusion and degradation of autophagolysosomes within the cells, interfering with Plasmodium reproduction.

-Autophagy Mechanism

Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are the only two FDA-approved autophagy inhibitors.

- Pro-apoptotic Mechanism

It has been reported that chloroquine can enhance the in vitro effects of PI3K/AKT/mTOR inhibitors on mouse breast cancer cells 67NR and 4T1.

Chloroquine can activate apoptosis in cancer cells independently of autophagy inhibition.

-Anti-inflammatory Mechanism

Chloroquine can reduce the production and release of pro-inflammatory cytokines through multiple pathways, thereby exerting immunomodulatory effects. These pathways include the inhibition of Toll-like receptors, endolysosomal activity, the release of inflammatory cytokines, NADPH oxidase (NOX) activity, and calcium (Ca2?) signaling.

Application

1. Antimalarial

2. Antitumor

3. Immunological diseases

4. Antiviral research

References

[1]Liu Y, Meng Y, Zhang J, et al. Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy. Int J Nanomedicine. 2024;19:6777-6809. Published 2024 Jul 5. doi:10.2147/IJN.S458910

[2]Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24(8):560-575. doi:10.1038/s41580-023-00585-z

[3]Nirk EL, Reggiori F, Mauthe M. Hydroxychloroquine in rheumatic autoimmune disorders and beyond. EMBO Mol Med. 2020;12(8):e12476. doi:10.15252/emmm.202012476

[4]Agalakova NI. Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment. Int J Mol Sci. 2024;25(2):945. Published 2024 Jan 12. doi:10.3390/ijms25020945

[5]Liu Y, Meng Y, Zhang J, et al. Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy. Int J Nanomedicine. 2024;19:6777-6809. Published 2024 Jul 5. doi:10.2147/IJN.S458910

[6]Boelaert JR, Piette J, Sperber K. The potential place of chloroquine in the treatment of HIV-1-infected patients. J Clin Virol. 2001;20(3):137-140. doi:10.1016/s1386-6532(00)00140-2

[7]Dowall SD, Bosworth A, Watson R, et al. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model. J Gen Virol. 2015;96(12):3484-3492. doi:10.1099/jgv.0.000309

[8]Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020;177:104762. doi:10.1016/j.antiviral.2020.104762