Fig. 1: Rational design of SARS-CoV-2 PLpro inhibitors and PK profiling. | Nature Communications

Fig. 1: Rational design of SARS-CoV-2 PLpro inhibitors and PK profiling.

From: Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

Fig. 1

a Analysis of potential ligand binding sites S1 and S2 (PDB: 7JRN). The critical hydrogen bonds between GRL0617 and PLpro are shown as marine dash lines. GRL0617 and the key residues of the ligand binding pocket are shown as cyan sticks and wheat sticks, respectively. b Strategies of structure-guided compound design. The optimized groups are shown as colored circles, bright orange for hydrophobicity, and split pea for hydrophilicity. c Procedures of activity optimization and in vitro PK optimization indicated by the representative compounds. d The inhibition activity on SARS-CoV-2 PLpro of the representative compounds. Data are presented as mean of two (GZNL-P1, GZNL-P3, GZNL-P17, GZNL-P35, and GZNL-P36) or three (GRL0617 and GZNL-P4) technical replicates. Three independent experiments were tested and shown in Supplementary Table 3, only one representative is shown here. e The in vivo PK profiling of GZNL-P35 and GZNL-P36 at 10 mg/kg and 20 mg/kg (n = 3 per group). f The in vitro stability in liver microsome of the representative compounds. g Summary of in vivo PK, metabolism, distribution, and toxicity properties of GZNL-P36. Source data of (d) and (e) are provided as a Source Data file.

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