The PIKfyve Inhibitor Apilimod: A Double-Edged Sword against COVID-19

Abstract

The PIKfyve inhibitor apilimod is currently undergoing clinical trials for treatment of COVID-19. However, although apilimod might prevent viral invasion by inhibiting host cell proteases, the same proteases are critical for antigen presentation leading to T cell activation and there is good evidence from both in vitro studies and the clinic that apilimod blocks antiviral immune responses. We therefore warn that the immunosuppression observed in many COVID-19 patients might be aggravated by apilimod.

Keywords: COVID-19; LAM-002A; PIKfyve; SARS-CoV-2; STA-5326; apilimod.

Figure 1

SARS-CoV-2 and apilimod both inhibit the immune system in a similar manner. (A) Scheme of the viral S protein indicating the functional domains and the two proteolytic activation sites S1/2 and S2′. Apilimod, an inhibitor of PIKfyve, interferes with the endo/lysosomal trafficking and can indirectly block the activation of proteases as shown for Cathepsin B and L. Apilimod thereby likely interferes with proteolytic activation of the S protein and prevents host cell invasion. (B) Both upon infection with SARS-CoV-2 and upon exposure to apilimod, antigen presenting cells (APC) express lower levels of surface MHC class II (HLA-DR; MHCII) and produce less type I interferons (INF-α/β).