Brown University-Rhode Island Scientists Finds That Chitinase 3-Like-1 (CHI3L1) Inhibitors Stops Replication Of SARS-CoV-2 Including Omicron In Human Host
: Scientists from Brown University-Rhode Island have found that that Chitinase 3-Like-1 (CHI3L1) inhibitors stops replication of the SARS-CoV-2 coronavirus including the Omicron and Delta variants in the human host.
Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secreted glycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1 gene. The name YKL-40 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. YKL-40 is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells, vascular smooth muscle cells, and hepatic stellate cells. The biological function of YKL-40 is unclear. It is not known to have a specific receptor. Its pattern of expression is associated with pathogenic processes related to inflammation, extracellular tissue remodeling, fibrosis and solid carcinomas and asthma.
Evaluation of early SARS-CoV-2 strains suggested limited viral genetic diversity. However, genetic and epidemiologic investigations in the interim have revealed impressive genetic variability. Many of these viral variants are now defined as variants of concern (VOC) based on genetic alterations in their spike (S) and other proteins that cause enhanced transmissibility, decreased susceptibility to antibody neutralization or therapeutics and or their ability to induce severe disease.
The Delta and Omicron variants are particularly problematic based on their impressive and unprecedented transmissibility and ability to cause break through infections. The Delta variant also accumulates at high concentrations in host tissues and has caused waves of lethal disease. SARS-CoV-2 infection is mediated by S protein binding to cellular ACE2 receptors and subsequent S protein protease processing. Because studies from the laboratory of the study team have demonstrated that chitinase 3-like-1 (CHI3L1) stimulates ACE2 and S priming proteases, studies were undertaken to determine if interventions that target CHI3L1 are effective inhibitors of SC2 viral variant infection.
The study team demonstrated that CHI3L1 augments epithelial cell infection by pseudoviruses that express the alpha, beta, gamma, delta or omicron S proteins and that the CHI3L1 inhibitors: anti-CHI3L1 and kasugamycin inhibit epithelial cell infection by these VOC pseudovirus moieties. Hence, CHI3L1 is a universal, VOC-independent therapeutic target in COVID 19.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.01.21.477274v1
Typically, SARS-CoV-2 infection is caused by the spike (S) protein binding to cellular angiotensin-converting enzyme 2 (ACE2) receptors, which is subsequently processed by the S protein protease (SPP).
One recent study has found that chitinase 3-like-1 (CHI3L1) promotes ACE2 and SPPs. The researchers from that study have recently published new researchers, wherein they determining whether CHI3L1-targeted therapies are efficient inhibitors of SC2 viral variant infection. https://pubmed.ncbi.nlm.nih.gov/33442679/
The study team from the current research showed that the CHI3L1 inhibitors such as anti-CHI3L1 and Kasugamycin (KSM) reduce epithelial cell infection by VOC pseudovirus moieties that express the Alpha, Beta, Gamma, Delta, or Omicron S proteins. Both anti-CHI3L1 and KSM were also found to inhibit
epithelial cell infection by these VOC pseudovirus moieties.
It has been found that CHI3L1 is a powerful promoter of epithelial production of ACE2 and SPPs, as well as epithelial cell viral uptake.
The COVID-19 Drugs
study team investigated the absorption of VOC pseudoviruses with ancestral and mutant S proteins by untreated and CHI3L1-treated Calu-3 cells to determine whether the major S variations impacted these responses.
The study findings suggest that CHI3L1 was an effective activator of pseudovirus uptake with the ancient G614 S protein. When the S proteins from the Alpha, Beta, or Gamma variants were used, similar increases in Calu-3 cell pseudovirus uptake were observed. In fact, when the ancestral D614G and Alpha, Beta, or Gamma S protein mutations are present, CHI3L1 increases SARS-CoV-2 pseudovirus absorption when.
The inhibitory effects of the monoclonal anti-CHI3L1 antibody "FRG" on the absorption of pseudovirus by Calu-3 cells was assessed by treating the cells with and without CHI3L1. Treatment of Calu-3 cells with rCHI3L1 increased pseudovirus uptake, which was inhibited by FRG, but not by the IgG control, as was shown with the ancestral G614 S protein mutation. Interestingly, FRG reduced pseudovirus uptake by Calu-3 cells, even when exogenous rCHI3L1 was not provided.
In experiments utilizing pseudoviruses with Alpha, Beta, Gamma, Delta, or Omicron S protein mutations, rCHI3L1 produced similar stimulatory effects. Importantly, FRG significantly reduced the absorption of pseudoviruses with each of the S mutations in cells treated with and without rCHI3L1.
The study findings demonstrate that monoclonal anti-CHI3L1 targeting exogenous and/or endogenous CHI3L1 efficiently blocks the absorption of pseudoviruses with ancestral and all VOC protein mutations.
Kasugamycin or KSM is an aminoglycoside antibiotic that is a novel small molecule with potent anti-chitinase 1 (CHIT1) properties. https://en.wikipedia.org/wiki/Kasugamycin
Because CHIT1 and CHI3L1 are both members of the 18-glycohydrolase family, the study team wanted to determine whether KSM inhibits CHI3L1 activity in the same way as CHIT1 does. To this end, KSM treatment of Calu-3 cells inhibited CHI3L1-stimulated extracellular receptor kinase (ERK) and protein kinase B AKT activation, thereby indicating that KSM has potent anti-CHI3L1 activity.
The efficacy of Kasugamycin or KSM to change the SARS-CoV-2 Delta and Omicron variants’ ability to infect human epithelial cells was also tested.
Already CHI3L1 was found to be an effective activator of the uptake of pseudoviruses with Delta and Omicron S protein mutations however this increase was stopped by KSM, but not by the vehicle control. Even when exogenous CHI3L1 was not used, KSM reduced pseudovirus absorption by Calu-3 cells.
Detailed immunocytochemical tests supported these study findings, wherein the study team demonstrated that CHI3L1 increased ACE2 accumulation and Delta pseudovirus infection in Calu-3 cells. FRG was also found to suppress the expression of both Delta and Omicron pseudovirus infection both before and after rCHI3L1 injection.
Collectively, these results show that Kasugamycin or KSM targeting exogenous or endogenous CHI3L1 effectively suppresses the absorption of pseudoviruses with Alpha, Beta, Gamma, Delta, or Omicron S protein mutations.
The study findings add to the knowledge of early-stage SARS-CoV-2 therapeutics by demonstrating that the inhibition of ChI3L1 with FRG and/or Kasugamycin reduces the infection caused by the Alpha, Beta, Gamma, Delta, and Omicron SARS-CoV-2 variants. This suggests the intriguing prospect that FRG or Kasugamycin, alone or in combination with each other or other SARS-CoV-2 monoclonal antibodies, could have potent antiviral effects and/or limit viral infection in SARS-CoV-2-exposed individuals.
The study team also demonstrated that FRG and Kasugamycin can reduce viral replication and, as a result, illness pathophysiology and severity by lowering the viral load.
Although these findings are promising, more research into the significance of CHI3L1 and its role in infections induced by SARS-CoV-2 variants is needed.
For the latest on COVID-19 Drugs
, keep on logging to Thailand Medical News.