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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.
Kenji Ohwada,Tatsuo Fukuda,Jun’ichiro Mizuki,Kazuma Hirota,Hikaru Terauchi,Satoshi Tsutsui,Alfred Q. R. Baron,Hidehiro Ohwa,Naohiko Yasuda 한국물리학회 2011 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.59 No.31
Pb(In_(1/2)Nb_(1/2))O_3 (PIN) can be antiferroelectric (AFE), ferroelectric (FE) or a relaxor depending upon the perovskite B-site randomness. In order to clarify the effect of B-site randomness, we studied the dynamics of ordered PIN without B-site randomness (O-PIN, AFE), which will give us a clear picture of the AFE/relaxor nature of the ground state due to B-site randomness. The quasielastic (QE) scattering shows a critical slowing down near the Γ-point and the transverse acoustic (TA) mode shows a softening trend at a finite wavenumber position (not at the Γ-point) towards the AFE phase transition temperature (T_N ∼ 450 K). On the other hand, the transverse optic (TO) mode shows a softening near the Γ-point toward low temperature with no clear anomaly at T_N. These results indicate that the AFE phase transition is associated with the TA mode and the origin of the QE scattering while a ferroelectric correlation exists behind the AFE ordering. The effect of B-site randomness is finally discussed on the basis of the results.