The structure-based design of peptidomimetic inhibitors against SARS-CoV-2 3C like protease as Potent anti-viral drug candidate

Wang, Hao; Pei, Rongjuan; Li, Xin; Deng, Weilong; Xing, Shu; Zhang, Yanan; Zhang, Chen; He, Shuai; Sun, Hao; Xiao, Shuqi; Xiong, Ji; Zhang, Yecheng; Chen, Xinwen; Wang, Yaxin; Guo, Yu; Zhang, Bo; Shang, Luqing

doi:10.1016/j.ejmech.2022.114458

Cited by 18 publications

(19 citation statements)

References 23 publications

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“… 20 In addition, several other M pro inhibitors have been developed to date. 21 , 22 , 23 , 24 , 25 , 26 , 27 As the development of additional several drugs is required for a repertory of drug choice, we have tried to develop other M pro inhibitors. Previously, we characterized a hit compound, 5h ( 2 ), as a SARS-CoV-2 M pro inhibitor 19 among a panel of known compounds, which had originally shown inhibitory activity against SARS-CoV ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Tsuji¹,

Ishii²,

Kobayakawa³

et al. 2022

iScience

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Section: Introductionmentioning

confidence: 99%

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Tsuji¹,

Ishii²,

Kobayakawa³

et al. 2022

iScience

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“…As described in previous studies, − α-alkylation of 1 via deprotonation with lithium bis(trimethylsilyl)amide (LiHMDS) and the reaction of the enolate intermediate with bromoacetonitrile afforded cyanomethylglutamate 2 in only 60% yield along with syn-isomer 2I (3.5 A% HPLC) and intramolecular condensation reaction byproducts 2A and 2B (∼10 A% HPLC). A previous report on the use of Lewis acids to promote challenging Grignard additions to ketone substrates and the use of LaCl 3 ·2LiCl to stabilize the lactol product prompted us to investigate the effect of Lewis acid as an additive for α-cyanomethylation of the N -Boc- l -glutamate dimethyl ester ( 1 ) (Table ).…”

Section: Resultsmentioning

confidence: 83%

“…Existing methods for preparing cyclic glutamine analog 5 use multistep reactions starting from the N -Boc- l -glutamate 1,5-dimethyl ester (Scheme A). Initially, the preparation of cyanomethylglutamate 2 started from stereoselective cyanomethylation at the α-carbon of the N -Boc- l -glutamate 1,5-dimethyl ester. − The next two steps were as follows: reduction of the cyano group to a primary amine and cyclization onto the adjacent methyl ester to produce lactam ester 3 . The reported synthetic yields of the lactam ester 3 varied from 30% to 65% over the three steps. − Subsequent ammonolysis of lactam ester 3 resulted in amide 4 , which underwent N -Boc deprotection to generate cyclic glutamine analog 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Initially, the preparation of cyanomethylglutamate 2 started from stereoselective cyanomethylation at the α-carbon of the N -Boc- l -glutamate 1,5-dimethyl ester. − The next two steps were as follows: reduction of the cyano group to a primary amine and cyclization onto the adjacent methyl ester to produce lactam ester 3 . The reported synthetic yields of the lactam ester 3 varied from 30% to 65% over the three steps. − Subsequent ammonolysis of lactam ester 3 resulted in amide 4 , which underwent N -Boc deprotection to generate cyclic glutamine analog 5 . Recently, Vederas et al reported an alternative method for preparing cyclic glutamine analog 9 in multiple steps using the highly toxic reagent osmium tetroxide (Scheme B) .…”

Section: Introductionmentioning

confidence: 99%

“…We set out to improve the synthesis of 5 using approach A − (Scheme A). In the α-cyanomethylation of dimethyl N -BocGlu 1 and subsequent reduction of the cyano group, undesired byproducts were formed and contributed to the low yield of intermediate 3 (∼40% yield over two steps).…”

Section: Introductionmentioning

confidence: 99%

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Optimized Synthesis of a Key Intermediate of Nirmatrelvir

Qin

Chen

Odilov

et al. 2022

Org. Process Res. Dev.

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In this study, the development of a concise alternative process for synthesis of a key nirmatrelvir intermediate cyclic glutamine analog is described. The process proceedes via α-cyanomethylation of dimethyl N-BocGlu in the presence of NdCl 3 , followed by one-pot Raney nickel-catalyzed hydrogenation of the cyano group with concomitant cyclization and ammonolysis and subsequent deprotection of N-Boc to deliver the target intermediate cyclic glutamine analog in three steps with an 82% overall yield and 99.4 A% high-performance liquid chromatography (HPLC) purity. This study resulted in improved synthetic efficiency and stereoselectivity of α-cyanomethylation for production of a key nirmatrelvir intermediate cyclic glutamine analog.

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Applying the bioisosterism strategy to obtain lead compounds against SARS‐CoV‐2 cysteine proteases: An in‐silico approach

Borba,

de Araújo,

Veloso

et al. 2023

J Comput Chem

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SARS‐CoV‐2 cysteine proteases are essential nonstructural proteins due to their role in the formation of the virus multiple enzyme replication‐transcription complex. As a result, those functional proteins are extremely relevant targets in the development of a new drug candidate to fight COVID‐19. Based on this fact and guided by the bioisosterism strategy, the present work has selected 126 out of 1050 ligands from DrugBank website. Subsequently, 831 chemical analogs containing bioisosteres, some of which became structurally simplified, were created using the MB‐Isoster software, and molecular docking simulations were performed using AutoDock Vina. Finally, a study of physicochemical properties, along with pharmacokinetic profiles, was carried out through SwissADME and ADMETlab 2.0 platforms. The promising results obtained with the molecules encoded as DB00549_BI_005, DB04868_BI_003, DB11984_BI_002, DB12364_BI_006 and DB12805_BI_004 must be confirmed by molecular dynamics studies, followed by in vitro and in vivo empirical tests that ratify the advocated in‐silico results.

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The structure-based design of peptidomimetic inhibitors against SARS-CoV-2 3C like protease as Potent anti-viral drug candidate

Cited by 18 publications

References 23 publications

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Optimized Synthesis of a Key Intermediate of Nirmatrelvir

Applying the bioisosterism strategy to obtain lead compounds against SARS‐CoV‐2 cysteine proteases: An in‐silico approach

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