An ACAT inhibitor regulates SARS-CoV-2 replication and antiviral T cell activity

Abstract

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies have uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 entry and fusion independent of transmembrane protease serine 2 expression in multiple cell types. We also demonstrate a role for ACAT in regulating SARS-CoV-2 RNA replication in primary bronchial epithelial cells. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled in the acute phase of infection. Thus, re-purposing of available ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects.

Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture

“…As mentioned, prior models speculated that HCQ inhibits cathepsin-L by changing the endosomal pH 46 . While we did not actually test if SARS2-PV reaches the endosome, the lack of access to endocytic lipids in the HCQ-treated cells suggests that the virus may never reach cathepsin-L, and blocking cholesterol uptake appears to inhibit viral entry 76 . Another model suggests that HCQ could inhibit the SARS-COV-2 viral entry step by changing the glycosylation of membrane proteins 77,78 .…”

Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential

“…Though the clinical development of “imibes” (avasimibe, pactimibe and eflucimibe) was discontinued, the combination therapy of SOAT inhibitors with statins or similar agents may offer synergism in ameliorating atherosclerotic lesions and modulating cholesterol. Over the past few years, emerging research on SOAT inhibitors has been more intriguing and encouraging to the point where this target has hopes of being revived. , In the current era of drug discovery, sophisticated systems-biology approaches, the availability of “omics” data, and advances in AI/ML tools may yet rekindle interest in SOAT, leading to the approval of new drugs for curing SOAT-implicated pathologies.…”

“…Further, it was shown that the blockade of SOAT with avasimibe inhibits SARS-CoV-2 entry and fusion independent of transmembrane protease serine 2 (TMPRSS2) expression in multiple cell types. SOAT played a significant role in regulating SARS-CoV-2 RNA replication in primary bronchial epithelial cells, and avasimibe boosted the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection …”

“…Recent research revealed that T cell activity and the SARS-CoV-2 life cycle both include cholesterol metabolism. In many cell types, avasimibe ( 86 ) prevented the entrance and fusion of SARS-CoV-2 by suppressing SOAT …”