Ionophore Antibiotics Inhibit Type II Feline Coronavirus Proliferation In Vitro.

Feline coronaviruses (FCoVs) infect cats worldwide and cause severe systemic diseases, such as feline infectious peritonitis (FIP). FIP has a high mortality rate, and drugs approved by the Food and Drug Administration have been ineffective for the treatment of FIP. Investigating host factors and the functions required for FCoV replication is necessary to develop effective drugs for the treatment of FIP. FCoV utilizes an endosomal trafficking system for cellular entry after binding between the viral spike (S) protein and its receptor. The cellular enzymes that cleave the S protein of FCoV to release the viral genome into the cytosol require an acidic pH optimized in the endosomes by regulating cellular ion concentrations. Ionophore antibiotics are compounds that form complexes with alkali ions to alter the endosomal pH conditions. This study shows that ionophore antibiotics, including valinomycin, salinomycin, and nigericin, inhibit FCoV proliferation in vitro in a dose-dependent manner. These results suggest that ionophore antibiotics should be investigated further as potential broad-spectrum anti-FCoV agents.

Zinc ionophores: chemistry and biological applications.

Zinc can play a pathophysiological role in several diseases and can interfere in key processes of microbial growth. This evidence justifies the efforts in applying Zinc ionophores to restore Zinc homeostasis and treat bacterial/viral infections such as coronavirus diseases. Zinc ionophores increase the intracellular concentration of Zinc ions causing significant biological effects. This review provides, for the first time, an overview of the applications of the main Zinc ionophores in Zinc deficiency, infectious diseases, and in cancer, discussing the pharmacological and coordination properties of the Zinc ionophores.

Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?

In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection.

Ionophore antibiotic X-206 is a potent inhibitor of SARS-CoV-2 infection in vitro.

Pandemic spread of emerging human pathogenic viruses, such as the current SARS-CoV-2, poses both an immediate and future challenge to human health and society. Currently, effective treatment of infection with SARS-CoV-2 is limited and broad spectrum antiviral therapies to meet other emerging pandemics are absent leaving the World population largely unprotected. Here, we have identified distinct members of the family of polyether ionophore antibiotics with potent ability to inhibit SARS-CoV-2 replication and cytopathogenicity in cells. Several compounds from this class displayed more than 100-fold selectivity between viral-induced cytopathogenicity and inhibition of cell viability, however the compound X-206 displayed >500-fold selectivity and was furthermore able to inhibit viral replication even at sub-nM levels. The antiviral mechanism of the polyether ionophores is currently not understood in detail. We demonstrate, e.g. through unbiased bioactivity profiling, that their effects on the host cells differ from those of cationic amphiphiles such as hydroxychloroquine. Collectively, our data suggest that polyether ionophore antibiotics should be subject to further investigations as potential broad-spectrum antiviral agents.