Fig. 3: T22 potently inhibits the activity of TMPRSS2. | Nature Communications

Fig. 3: T22 potently inhibits the activity of TMPRSS2.

From: The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies

Fig. 3

a Flowcharts of the scFv phage library panning and antibody selection process. The number within parentheses indicates the quantity of phage and scFv-Fc antibodies that were tested. b Dose‒response curve illustrating T22-mediated inhibition of TMPRSS2 catalytic activity. The data points represent the means ± standard deviations (SDs) from biological quadruplicates (n = 4). Error bars may not be visible because of their small magnitude relative to the data points. c Binding of T22 to TMPRSS2 measured by BLI. Biotinylated TMPRSS2 was immobilized on SA biosensors and then exposed to twofold dilutions of T22. d Effect of T22 on HCoV-HKU1-mediated cell‒cell fusion. The data points represent the means ± SDs from biological triplicates (n = 3). e Vero E6-TMPRSS2 cells were pretreated with different concentrations of T22 for 1 h and then infected with wild-type SARS-CoV-2 or its delta variant (MOI = 0.01). The cytopathic effect (CPE) rates were determined with a Celigo image cytometer at 72 h post-infection. The data points represent the means ± SDs from biological triplicates (n = 3). f Crystal structure of the T22 Fab in complex with TMPRSS2. TMPRSS2 is depicted with its SP domain in mint, whereas its LDLRA and SRCR domains are colored slate. The Cα atom of residue 441 in TMPRSS2 is represented by a hot pink sphere. The T22 heavy chain is shown in dark gray, with its CDRs in orange. The T22 light chain is displayed in light gray, with its CDRs in marine blue. g Structural comparison between the RBD:TMPRSS2 and T22:TMPRSS2 complexes. TMPRSS2 from both structures are aligned, with only TMPRSS2 from the T22:TMPRSS2 complex shown owing to negligible conformational changes between the two structures. TMPRSS2 is displayed as a surface representation, whereas RBD and T22 are shown as cartoons. h, i Zoomed-in views of the interactions between T22 and TMPRSS2. j Illustration of CDRH3 binding in the TMPRSS2 substrate-binding pocket. The structure of the peptidomimetic inhibitor Ac-KQLR-cmk in complex with TMPRSS1 (homologous to TMPRSS2, PDB ID: 1Z8G) is superimposed. The inhibitor and catalytic serine residue S353 are shown as deep blue sticks. Panel (a) was created in BioRender. Duan, Y. (2025) https://BioRender.com/ul5s7vf.

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