Understanding genetic susceptibility to and druggability of COVID-19

Potential genetic predisposition for increased risk of COVID-19

Severe acute respiratory syndrome coronaviruses (SARS-CoV-1 and SARS-CoV-2) are unique among coronaviruses because they target the ACE2 receptor and the TMPRSS2 protease required for priming the coronavirus spike protein for viral entry. The concept of blocking entry is not new and is one of the main approaches used to treat AIDS with the HIV entry inhibitor Enfurvirtide.

The ACE2 receptor protein is expressed in the lung, intestines, adrenal, heart, kidney, gallbladder, and testis (Human protein atlas, Entrez Gene), but ACE2 expression in oral mucosal cells and tongue are an environmentally accessible cavity and entry point for SARS-CoV-2.

The progression to COVID-19 symptoms is highly variable, with many asymptomatic people, some having extreme morbidly, and for others the disease is lethal. It is not yet known but there may be a genetic predisposition for increased risk of COVID-19 and more severe outcomes. This is indeed supported by the variable mortality in different countries that have different ethnic populations. Therefore, we examined the variability of ACE2 functional genetics in the human population to assess the potential genetic susceptibility to COVID-19 as previously suggested.

The ACE2 protein has structural contacts with the SARS-CoV2 spike protein through amino acids E23, Q24, T27, D30, H34, D38, Y41, L79, M82, Y83, N330, N338, Y449, or K353 (PDBid: 6M0J). We can estimate the frequency of mutation in these residues from approximately 220,000 people in the GnomAD database. ACE2 polymorphisms are known in approximately 3.3% of the population and polymorphisms in four of the contact residues (E23, T27, M82, and N338) are rare (0.006%). If we also consider variation in juxtaposed amino acids that are also likely to influence binding, this represents only 0.4% of the population.

Crystal structure of ACE2 Receptor Protein and the SARS-CoV-2 Spike Protein

Protein Databank structure of ACE2 Receptor (green) and SARS-CoV-2 Spike Protein (brown) (PDB: 6M0J)

The elements that affect ACE2 expression and COVID-19 clinical consequences

Although some variability in the ACE2 coding region may explain some of the variable COVID-19 presentations, other ACE2 genetic elements affect its expression and impact COVID-19 function and clinical consequences. Several conditions and factors related to COVID-19 illness include hypoxia, angiotensin peptides, cytokines, steroid hormones as well as the HNF transcription factor, and AMP kinase known to control ACE2 expression levels.

Some experts think down-regulation of the ACE2 receptor increases angiotensin II levels contributing to COVID mortality. At this point, very little is known about the ACE2 promoter. Genetic variation in the ACE2 promoter and 3’ UTR may underlie differential expression levels of ACE2 among people. Indeed, there is significant known variability in these regions with 479 variants in dbSNP.

The impact of all these variants and those that have not yet been discovered are not yet known. This is precisely one way where Heligenics can help with the response to the COVID-19 pandemic. Heligenics can produce Gene Mutation/Function libraries (GML)s for all variants in the promoter and 3’ UTR that affect gene expression and in the coding region that affects binding of SARS-CoV2. These GMLs can be important for understanding COVID-19 pathogenesis and then genetic testing for COVID-19 susceptibility and prognosis.
Heligenics GMLs can also help address the COVID pandemic by examining coding regions of viral and host drug targets to improve drug design, by using functional genetic data to increase efficiency, reduce cellular toxicity, and guide genetic-based clinical trial design. GMLs of the viral promoter could help identify essential viral regions for genome editing-based therapies and identify novel host transcription factor targets.

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