ABSTRACT
Since chloroquine (CQ) and hydroxychloroquine (HCQ) can inhibit the invasion and proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured cells, the repurposing of these antimalarial drugs was considered a promising strategy for treatment and prevention of coronavirus disease (COVID-19). However, despite promising preliminary findings, many clinical trials showed neither significant therapeutic nor prophylactic benefits of CQ and HCQ against COVID-19. Here, we aim to answer the question of why these drugs are not effective against the disease by examining the cellular working mechanisms of CQ and HCQ in prevention of SARS-CoV-2 infections.
Subject(s)
COVID-19 Drug Treatment , Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/virology , Cell Proliferation/drug effects , Chloroquine/adverse effects , Drug Repositioning , Humans , Hydroxychloroquine/adverse effects , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicityABSTRACT
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.
Subject(s)
Antiviral Agents/adverse effects , COVID-19 Drug Treatment , Hydrazones/adverse effects , Morpholines/adverse effects , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/adverse effects , Pyrimidines/adverse effects , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/immunology , Humans , Hydrazones/pharmacology , Morpholines/pharmacology , Peptide Hydrolases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Protease Inhibitors/pharmacology , Pyrimidines/pharmacology , Serine Endopeptidases/metabolismABSTRACT
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.