Abstract
Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways by removing ubiquitin and/or ISG15 from proteins using a protease called PLpro, but also by interacting with enzymes involved in ubiquitin/ISG15 machinery. These enable viral replication and avoidance of the host immune system. In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host–pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease.
Highlights
Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses that cause the common cold in a broad range of mammals and avians [1]
Paxlovid has just been approved by the U.S Food and Drug Administration issued with an emergency use authorization (EUA) and by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK
SARS-CoV-2 is a positive-sense single-stranded RNA virus, and it is the causative virus of COVID-19 in humans
Summary
Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses that cause the common cold in a broad range of mammals and avians [1]. Severe infection can lead to respiratory and multi-organ failure, as well as digestive and neurological insults [2]. This was previously evidenced with the emergence of the pathogens responsible for Severe. Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2002 [3], and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 [4] Both diseases were linked to zoonotic origins and resulted in a highly contagious and sometimes lethal acute respiratory illness. Despite the success of global vaccine rollouts, several mutated variants of SARS-CoV-2 have evolved, resulting in subtle changes in disease indications and strengths of transmissibility [6]. We discuss how the machinery involved in ubiquitylation and ISGylation can be utilized for the development of novel therapeutics against SARS-CoV-2 infection
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