TY - JOUR
T1 - Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds
T2 - Design, synthesis, biological evaluation, and docking studies
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 - 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 Scientists ( Tokubetsu Kenkyuin Shorei-hi ) 23·01104 and a Grant-in-aid for Scientific Research 23659059 . E.F. acknowledges support from the National Institutes of Health (Grants GM57144 and GM56550 ) and from the National Science Foundation ( MCB-1157506 ).
PY - 2013
Y1 - 2013
N2 - We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
AB - We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
KW - Cysteine protease inhibitors
KW - Dipeptide
KW - Peptidomimetics
KW - SARS
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U2 - 10.1016/j.ejmech.2013.07.037
DO - 10.1016/j.ejmech.2013.07.037
M3 - Article
C2 - 23994330
AN - SCOPUS:84882798645
VL - 68
SP - 372
EP - 384
JO - CHIM.THER.
JF - CHIM.THER.
SN - 0223-5234
ER -