Targeting the sAC-Dependent cAMP Pool to Prevent SARS-Cov-2 Infection

Abstract

An outbreak of the novel coronavirus (CoV) SARS-CoV-2, the causative agent of COVID-19 respiratory disease, infected millions of people since the end of 2019, led to high-level morbidity and mortality and caused worldwide social and economic disruption. There are currently no antiviral drugs available with proven efficacy or vaccines for its prevention. An understanding of the underlying cellular mechanisms involved in virus replication is essential for repurposing the existing drugs and/or the discovery of new ones. Endocytosis is the important mechanism of entry of CoVs into host cells. Endosomal maturation followed by the fusion with lysosomes are crucial events in endocytosis. Late endosomes and lysosomes are characterized by their acidic pH, which is generated by a proton transporter V-ATPase and required for virus entry via endocytic pathway. The cytoplasmic cAMP pool produced by soluble adenylyl cyclase (sAC) promotes V-ATPase recruitment to endosomes/lysosomes and thus their acidification. In this review, we discuss targeting the sAC-specific cAMP pool as a potential strategy to impair the endocytic entry of the SARS-CoV-2 into the host cell. Furthermore, we consider the potential impact of sAC inhibition on CoV-induced disease via modulation of autophagy and apoptosis.

Curcumin as a Potential Treatment for COVID-19

“…The entry of SARS-CoV-2 through the endosome requires an endosomal environment with an acidic pH that is promoted by the endosomal proteases, cathepsin B and L, and ion channels, particularly the vacuolar ATPase pump (V-ATPase), which is crucial in regulating endosomal pH (Aslam and Ladilov, 2020;Khan et al, 2020). Curcumin has been shown to be a potential pH controlling agent, decreasing the expression of V-ATPase, which causes an increase in pH in tumor cells (Vishvakarma et al, 2011).…”

Emerging insights on the role of V‐ATPase in human diseases: Therapeutic challenges and opportunities

“…Research on this topic exploded and several strategies to treat the associated diseases are being proposed by scientists worldwide. Some of them include the repurposing of clinically approved drugs that target the lysosomal/endosomal pH aiming to block viral entry and replication 313 . Promising examples include the antimalarial drug chloroquine, which increases the pH of these compartments and that was demonstrated to impair entry and replication of SARS‐CoV‐2 in kidney Vero E6 cells, 314 and to inhibit pneumonia exacerbation and decrease disease course in COVID‐19 patients 315 ; the antipsychotic drug chlorpromazine, which hinders clathrin‐mediated endocytosis by interacting with dynamin, 316 and that showed activity against SARS‐CoV 317 and is planned to be included in a phase III trial to evaluate its anti‐SARS‐CoV‐2 activity 318 ; and the anti‐inflammatory drug cepharanthine, which was identified in a screening for drug repurposing against SARS‐CoV‐2 and completely inhibited the viral infection at the entry and post‐entry stages in an in vitro model using a SARS‐CoV‐2‐related pangolin coronavirus 319 .…”

A distinct metabolic profile associated with a fatal outcome in COVID-19 patients during early epidemic in Italy

“…The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101/2021.04.13.21255117 doi: medRxiv preprint 6 SARS-CoV-2 endocytosis in the initial phases of the infection [12], its involvement in disease progression is worthy of further investigations as a potential biomarker.…”

“…cAMP is a well-known intracellular messenger that functions as a regulator of various cellular activities, including cell growth and differentiation, gene transcription, protein expression, and is intimately involved in mitochondrial dynamics [11]. As cAMP plays a role in SARS-CoV-2 endocytosis in the initial phases of the infection [12], its involvement in disease progression is worthy of further investigations as a potential biomarker.…”