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Fig. 2 | BMC Medicine

Fig. 2

From: New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

Fig. 2

Structural view of the coding-region variants in ACE2 and TMPRSS2 and a proposed pharmacogenomics model of effective combination therapies for COVID-19. a Full-length structures of the sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19, red)–ACE2 (blue) heterodimer in its homodimeric form complexed with the receptor binding domain (RBD, mint) of SARS-CoV-2 (PDB ID: 6M17). Highly deleterious variants are labeled as yellow spheres on ACE2. Insets depict mutations in residues 383 through 427 (top) and residues 708 through 731 (bottom). b Homology model of the catalytic chain (256–492) of TMPRSS2. Highly deleterious mutations are labeled as yellow spheres. c A proposed model of effective combination therapies (i.e., hydroxychloroquine, E-64D (a protease inhibitor), and camostat mesylate (an approved TMPRSS2 for treatment of chronic pancreatitis in Japan)) for COVID-19 by blocking ACE2 and TMPRSS2 across different populations with three genotypes. Relationship among spike (S) protein of SARS-CoV-2, ACE2, and TMPRSS2 were shown as a triangle, with each pair connecting by physical binding (double-headed arrow) or cleavage (single-headed arrow). We propose three hypotheses for COVID-19 therapeutic options: (i) for patients with wild-type or naïve expression of ACE2 and TMPRSS2, hydroxychloroquine (or chloroquine, or E-64D) combined with camostat may offer more clinical benefit; (ii) for patients with polymorphisms or dysregulation on TMPRSS2, hydroxychloroquine or chloroquine monotherapy may offer more clinical benefit; and (iii) for patients with polymorphisms or dysregulation on ACE2, the patients who might have mild symptoms can recover in a short period. All three pharmacogenomics models for COVID-19 must be validated both experimentally and clinically before being used in patients

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