TY - JOUR
T1 - Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety
AU - Konno, Sho
AU - Thanigaimalai, Pillaiyar
AU - Yamamoto, Takehito
AU - Nakada, Kiyohiko
AU - Kakiuchi, Rie
AU - Takayama, Kentaro
AU - Yamazaki, Yuri
AU - Yakushiji, Fumika
AU - Akaji, Kenichi
AU - Kiso, Yoshiaki
AU - Kawasaki, Yuko
AU - Chen, Shen En
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.
PY - 2013/1/15
Y1 - 2013/1/15
N2 - We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CLpro. A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CLpro motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1′ site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC50 or K i values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K i values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CLpro may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1′-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
AB - We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CLpro. A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CLpro motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1′ site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC50 or K i values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K i values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CLpro may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1′-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
KW - Cysteine protease inhibitors
KW - Docking study
KW - Peptidomimetics
KW - SARS
KW - SARS-CoV 3CL protease
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U2 - 10.1016/j.bmc.2012.11.017
DO - 10.1016/j.bmc.2012.11.017
M3 - Article
C2 - 23245752
AN - SCOPUS:84871634551
SN - 0968-0896
VL - 21
SP - 412
EP - 424
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 2
ER -