The docked poses of '2222/'2602 predicted that these compounds could use their primary amines to specifically engage the TMPRSS2 S1 residues S436 and D435, and the amide bond present within these compounds was oriented away from the TMPRSS2 oxyanion hole to prevent proteolytic cleavage (Fig. ). The distal ends of '2222/'2602 were predicted to engage the TMPRSS2 S1' residues V280 and the C281-C297 disulfide (Fig. ). Interestingly, the S436 residue of TMPRSS2 is only partially conserved amongst human TTSPs and other trypsin-like serine proteases found in the blood, suggesting that '2222/'2602 could potentially exploit the S436 residue for TMPRSS2 selectivity (Extended Data Fig. ).