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Discovery of New Fusion Inhibitor Peptides against SARS-CoV-2 by Targeting the Spike S2 Subunit
( Mahmoud Kandeel ),( Mizuki Yamamoto ),( Hideki Tani ),( Ayako Kobayashi ),( Jin Gohda ),( Yasushi Kawaguchi ),( Byoung Kwon Park ),( Hyung-joo Kwon ),( Jun-ichiro Inoue ),( Abdallah Alkattan ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.3
A novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused a worldwide pandemic. Our aim in this study is to produce new fusion inhibitors against SARS-CoV-2, which can be the basis for developing new antiviral drugs. The fusion core comprising the heptad repeat domains (HR1 and HR2) of SARS-CoV-2 spike (S) were used to design the peptides. A total of twelve peptides were generated, comprising a short or truncated 24-mer (peptide #1), a long 36-mer peptide (peptide #2), and ten peptide #2 analogs. In contrast to SARS-CoV, SARS-CoV-2 S-mediated cell-cell fusion cannot be inhibited with a minimal length, 24-mer peptide. Peptide #2 demonstrated potent inhibition of SARS-CoV-2 S-mediated cell-cell fusion at 1 μM concentration. Three peptide #2 analogs showed IC50 values in the low micromolar range (4.7-9.8 μM). Peptide #2 inhibited the SARSCoV- 2 pseudovirus assay at IC50=1.49 μM. Given their potent inhibition of viral activity and safety and lack of cytotoxicity, these peptides provide an attractive avenue for the development of new prophylactic and therapeutic agents against SARS-CoV-2.
( Mahmoud Kandeel ),( Mizuki Yamamoto ),( Abdulla Al-taher ),( Aya Watanabe ),( Kentaro Oh-hashi ),( Byoung Kwon Park ),( Hyung-joo Kwon ),( Jun-ichiro Inoue ),( Mohammed Al-nazawi ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.4
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC<sub>50</sub> values of 12.6, 21.8, and 11.12 μM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 at a concentration of 20 μM with no observed toxicity in Vero cells at 10 μM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.
Yu, Jiyeon,Yun, Hyeongseok,Shin, Bongjin,Kim, Yongjin,Park, Eui-Soon,Choi, Seunga,Yu, Jungeun,Amarasekara, Dulshara Sachini,Kim, Sumi,Inoue, Jun-ichiro,Walsh, Matthew C.,Choi, Yongwon,Takami, Masamich American Society for Biochemistry and Molecular Bi 2016 The Journal of biological chemistry Vol.291 No.39
<P>The signaling pathway downstream of stimulation of receptor activator of nuclear factor B (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANK(cyto)) to trigger downstream osteoclastogenic signaling cascades. RANK(cyto) harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANK(cyto) mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANK(cyto) mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANK(cyto) enhances downstream NF-B, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.</P>