Dimethoxycurcumin Acidifies Endolysosomes and Inhibits SARS-CoV-2 Entry.

Area of Science:

• Virology
• Pharmacology
• Cell Biology

Background:

• Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, remains a global health crisis with limited therapeutic options.
• Curcumin shows antiviral properties but has poor bioavailability, hindering clinical use.

Purpose of the Study:

• To investigate the efficacy of dimethoxycurcumin (DiMC), a bioavailable curcumin analog, against SARS-CoV-2 entry.
• To elucidate the mechanism by which DiMC inhibits viral entry.

Main Methods:

• Assessed DiMC's effect on pseudo-SARS-CoV-2 entry into Calu-3 and Vero E6 cells.
• Analyzed DiMC's impact on lysosomal function and degradation of ACE2 and viral components.
• Evaluated other lysosome acidifying agents (ML-SA1, NS1619) for anti-SARS-CoV-2 activity.

Main Results:

• DiMC significantly blocked pseudo-SARS-CoV-2 entry into lung and kidney epithelial cells.
• DiMC acidified lysosomes, boosted their degradation capacity, and promoted breakdown of ACE2, pseudo-SARS-CoV-2, and the S1 protein.
• Lysosome acidifying agents ML-SA1 and NS1619 also inhibited pseudo-SARS-CoV-2 entry.

Conclusions:

• DiMC demonstrates potent anti-SARS-CoV-2 activity by targeting lysosomal pathways.
• Lysosome acidification emerges as a promising strategy for developing novel COVID-19 therapeutics.
• DiMC and similar agents warrant further investigation as potential COVID-19 treatments.