Infection of certain influenza viruses is triggered when its HA is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, whereas the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R↓ sequences. Here, we solved the crystal structure of the extracellular region of human MSPL in complex with an irreversible substrate-analog inhibitor. The structure revealed three domains clustered around the C-terminal α-helix of the SPD. The inhibitor structure and its putative model show that the P1-Arg inserts into the S1 pocket, whereas the P2-Lys and P4-Arg interacts with the Asp/Glu-rich 99-loop that is unique to MSPL. Based on the structure of MSPL, we also constructed a homology model of TMPRSS2, which is essential for the activation of the SARS-CoV-2 spike protein and infection. The model may provide the structural insight for the drug development for COVID-19.
AbstractViral infection is triggered when a surface envelope glycoprotein, hemagglutinin (HA), is cleaved by host cell proteins of the transmembrane protease serine (TMPRSS) family. The extracellular region of TMPRSS-2, -3, -4, and MSPL are composed of LDLA, SRCR, and SPD domains. MSPL can cleave the consensus multibasic (R-X-X/R-R) and monobasic (Q(E)-T/X-R) motifs on HA, while TMPRSS2 or -4 only cleaves monobasic motifs. To better understand HA cleavage mediated by MSPL, we solved the crystal structure of the extracellular region of human MSPL in complex with the furin inhibitor. The structure revealed that three domains are gathered around the C-terminal α-helix of the SPD domain. The furin inhibitor structure shows that the side chain of P1-Arg inserts into the highly conserved S1 pocket, whereas the side chain of P2-Lys interacts with the Asp/Glu-rich 99 loop that is unique to MSPL. We also constructed a homology model of TMPRSS2, which is identified as an initiator of SARS-CoV-2 infection. The model suggests that TMPRSS2 is more suitable for Ala/Val residues at the P2 site than Lys/Arg residues.
We developed a novel method for deprotecting the N-PMB group of carbazoles. The combination of PhI(OAc) 2 and N-hydroxyphthalimide cleaved the N-PMB group with moderate to good yields depending on the substituents on the carbazole ring.Carbazole is an important structure in natural products and pharmaceuticals with a variety of biological activities. 1 Carbazoles are also used in functional materials with interesting optical and electronic properties. 2 Therefore, various synthetic methods have been reported. 1a,1b,3 In some cases, a nitrogen atom
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