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 the AIDS with the HIV entry inhibitor Enfurvirtide.
The ACE2 receptor protein is expressed in 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 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.