Subject(s)
COVID-19 , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines/genetics , Humans , SARS-CoV-2ABSTRACT
Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1ß and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.
Subject(s)
Amines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Chloroquine/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amines/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , B-Lymphocytes/immunology , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Cytokines/metabolism , Dose-Response Relationship, Drug , Humans , Macrophages/drug effects , Macrophages/immunology , Microbial Sensitivity Tests , Molecular Structure , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a "clickable" NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus through the endolysosomal system. Thus, JPT2 is a component of the NAADP receptor complex that is essential for TPC-dependent Ca2+ signaling and control of coronaviral entry.