TY - JOUR
T1 - Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors
T2 - Structure-activity relationship study
AU - Thanigaimalai, Pillaiyar
AU - Konno, Sho
AU - Yamamoto, Takehito
AU - Koiwai, Yuji
AU - Taguchi, Akihiro
AU - Takayama, Kentaro
AU - Yakushiji, Fumika
AU - Akaji, Kenichi
AU - Kiso, Yoshiaki
AU - Kawasaki, Yuko
AU - Chen, Shen En
AU - Naser-Tavakolian, Aurash
AU - Schön, Arne
AU - Freire, Ernesto
AU - Hayashi, Yoshio
N1 - Funding Information:
This research was supported by Grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, including a Grant-in-aid for Young scientist ( Tokubetsu Kenkyuin Shorei-hi ) 23·01104 and a Grant-in-aid for Scientific Research 23659059 and 23390029 . E.F. acknowledges support from the National Institutes of Health (grant GM57144 ).
PY - 2013
Y1 - 2013
N2 - This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(-pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CLpro. In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1′ position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.
AB - This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(-pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CLpro. In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1′ position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.
KW - Cysteine protease inhibitors
KW - Dipeptide
KW - Docking study
KW - Peptidomimetics
KW - SARS
KW - SARS-CoV 3CL protease
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U2 - 10.1016/j.ejmech.2013.05.005
DO - 10.1016/j.ejmech.2013.05.005
M3 - Article
C2 - 23747811
AN - SCOPUS:84878735186
VL - 65
SP - 436
EP - 447
JO - CHIM.THER.
JF - CHIM.THER.
SN - 0223-5234
ER -