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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.
Activity of Some Hepatic Enzymes in Schistosomiasis and Concomitant Alteration of Arylsulfatase B
( Mahmoud Balbaa ),( Mohamed El Kersh ),( Hamdy Mansour ),( Galila Yacout ),( Mohamed Ismail ),( Ahmed Malky ),( Khaled Bassiouny ),( Nihad Abdel Monem ),( Kamal Kandeel ) 생화학분자생물학회 2004 BMB Reports Vol.37 No.2
The levels of arylsulfatases A and B, α-amylase, aspartate transcarbamylase, and γ-glutamyl transpeptidase were investigated during the infection of mice with schistosoma mansoni. This infection caused a significant (p<0.001) increase in the activity of hepatic arylsulfatases B (ASB), aspartate transcarbamylases and γ-glutamyl transpeptidase. A non-significant difference occurred for a-amylase (p<0.3) and arylsulfatases A(p>0.5) when compared to the control. The specific activity of hepatic ASB was progressively increased with the progression of the Schistosoma-infection. Moreover, the kinetic studies of hepatic ASB in Schistosoma-infection showed that a slight decrease in the value of K_(m) and about a 40% increase in V_(max) when compared to the control. In addition, the pH optimum of hepatic ASB was altered from 6 to 7 as a result of schistosomiasis. These observations suggest that there are schistosomiasis-associated changes of the catalytic and kinetic properties of hepatic ASB.
Activity of Some Hepatic Enzymes in Schistosomiasis and Concomitant Alteration of Arylsulfatase B
Balbaa, Mahmoud,El-Kersh, Mohamed,Mansour, Hamdy,Yacout, Galila,Ismail, Mohamed,Malky, Ahmed,Bassiouny, Khaled,Abdel-Monem, Nihad,Kandeel, Kamal Korean Society for Biochemistry and Molecular Biol 2004 Journal of biochemistry and molecular biology Vol.37 No.2
The levels of arylsulfatases A and B, $\alpha$-amylase, aspartate transcarbamylase, and $\gamma$-glutamyl transpeptidase were investigated during the infection of mice with schistosoma mansoni. This infection caused a significant (p<0.001) increase in the activity of hepatic arylsulfatase B (ASB), aspartate transcarbamylases and $\gamma$-glutamyl transpeptidase. A non-significant difference occurred for $\alpha$-amylase (p<0.3) and arylsulfatase A (p>0.5) when compared to the control. The specific activity of hepatic ASB was progressively increased with the progression of the Schistosoma-infection. Moreover, the kinetic studies of hepatic ASB in Schistosoma-infection showed that a slight decrease in the value of $K_m$ and about a 40% increase in $V_{max}$ when compared to the control. In addition, the pH optimum of hepatic ASB was altered from 6 to 7 as a result of schistosomiasis. These observations suggest that there are schistosomiasis-associated changes of the catalytic and kinetic properties of hepatic ASB.
Kim Jinsoo,Hwang Seok Young,Kim Dongbum,Kim Minyoung,Baek Kyeongbin,Kang Mijeong,An Seungchan,Gong Junpyo,Park Sangkyu,Kandeel Mahmoud,Lee Younghee,Noh Minsoo,Kwon Hyung-Joo 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.5
The drug repurposing strategy has been applied to the development of emergency COVID-19 therapeutic medicines. Current drug repurposing approaches have been directed against RNA polymerases and viral proteases. Recently, we found that the inhibition of the interaction between the SARS-CoV-2 structural nucleocapsid (N) and spike (S) proteins decreased viral replication. In this study, drug repurposing candidates were screened by in silico molecular docking simulation with the SARS-CoV-2 structural N protein. In the ChEMBL database, 1994 FDA-approved drugs were selected for the in silico virtual screening against the N terminal domain (NTD) of the SARS-CoV-2 N protein. The tyrosine 109 residue in the NTD of the N protein was used as the center of the ligand binding grid for the docking simulation. In plaque forming assays performed with SARS-CoV-2 infected Vero E6 cells, atovaquone, abiraterone acetate, and digoxin exhibited a tendency to reduce the size of the viral plagues without affecting the plaque numbers. Abiraterone acetate significantly decreased the accumulation of viral particles in the cell culture supernatants in a concentration-dependent manner. In addition, abiraterone acetate significantly decreased the production of N protein and S protein in the SARS-CoV-2-infected Vero E6 cells. In conclusion, abiraterone acetate has therapeutic potential to inhibit the viral replication of SARS-CoV-2.