Groundbreaking Study Unveils Novel Treatment for Blocking SARS-CoV-2 Entry into Cells

Abstract
The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells. UNI418 inhibited the proteolytic activation of cathepsins, which is regulated by PIKfyve, resulting in the inhibition of cathepsin L-dependent proteolytic cleavage of the SARS-CoV-2 spike protein into its mature form, a critical step for viral endosomal escape. We also demonstrated that UNI418 prevented ACE2-mediated endocytosis of the virus via PIP5K1C inhibition. Our results identified PIKfyve and PIP5K1C as potential antiviral targets and UNI418 as a putative therapeutic compound against SARS-CoV-2.

Despite the ongoing threat posed by new viruses following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to the coronavirus disease 2019 (COVID-19) pandemic, new antiviral drugs continue to be developed to effectively block viral entry into the human body.

Professor Kyungjae Myung and his research team in the Department of Biomedical Engineering, affiliated with the IBS Center for Genomic Integrity, has discovered UNI418, a compound that effectively prevents the penetration of the coronavirus. This compound works by regulating dielectric homeostasis, thereby inhibiting the virus’s entry into human cells.

Figure 1. Schematic image, showing the blockade of the endocytic pathway by UNI418 in SARS-CoV-2-infected cells.

SARS-CoV-2, the virus that causes COVID-19 enters cells through endocytosis, a process whereby human cells absorb material from the outside by engulfing it with their cell membrane. The research team demonstrated that inhibiting specific proteins called, PIKfyve and PIP5K1C during this process can help maintain dielectric homeostasis and prevent viral invasion.

Figure 2. The graphical model shows how UNI418 inhibits SARS-CoV-2 entry into cells by targeting PIP5K1C and PIKfyve.

Genomic homeostasis is the protective system that secures genetic information and allows it to be utilized when needed. The research team established that UNI418 supports genomic homeostasis while simultaneously preventing the infiltration and proliferation of coronaviruses within cells.

Existing treatments generally work by inhibiting viral proteins to prevent proliferation, but they are often less effective against mutant strains of the virus. This study represents the first evidence that UNI418 can disrupt the virus’s infection process, highlighting its potential as a treatment for mutant coronaviruses and other viral infections.

Co-researcher Joo-Yong Lee from Chungnam National University noted, “We proposed the potential of blocking the virus in the early stages of its entry into the human body.” Dr. Meheyein Kim from the Korea Research Institute of Chemical Technology (KRICT) added, “There is a high likelihood that UNI418 can develop into a new treatment paradigm that effectively blocks various viral infections.”

The findings were published in the online version of Experimental & Molecular Medicine (Nature Publishing Group), a prominent global medical journal on August 1, 2024.

Journal Reference
Yuri Seo, Yejin Jang, Seon-gyeong Lee, et al., “A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells,” Exp. Mol. Med., (2024).