A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease

被引：13

作者：

Geng, Zhi Zachary ^{[1
]}

Atla, Sandeep ^{[1
]}

Shaabani, Namir ^{[2
]}

Vulupala, Veerabhadra ^{[1
]}

Yang, Kai S. ^{[1
]}

Alugubelli, Yugendar R. ^{[1
]}

Khatua, Kaustav ^{[1
]}

Chen, Peng-Hsun ^{[1
]}

Xiao, Jing ^{[1
]}

Blankenship, Lauren R. ^{[1
]}

Ma, Xinyu R. ^{[1
]}

Vatansever, Erol C. ^{[1
]}

Cho, Chia-Chuan D. ^{[1
]}

Ma, Yuying ^{[1
]}

Allen, Robert ^{[2
]}

Ji, Henry ^{[2
]}

Xu, Shiqing ^{[1
,3
]}

Liu, Wenshe Ray ^{[1
,4
,5
,6
,7
]}

机构：

[1] Texas A&M Univ, Dept Chem, Texas A&M Drug Discovery Lab, College Stn, TX 77843 USA

[2] Sorrento Therapeut Inc, San Diego, CA 92121 USA

[3] Texas A&M Univ, Irma Lerma Rangel Coll Pharm, Dept Pharmaceut Sci, College Stn, TX 77843 USA

[4] Texas A&M Univ, Dept Chem, Dept Biochem & Biophys, Texas A&M Drug Discovery Lab, College Stn, TX 77843 USA

[5] Texas A&M Univ, Coll Med, Dept Mol & Cellular Med, College Stn, TX 77843 USA

[6] University, Inst Biosci & Technol, Houston, TX 77030 USA

[7] Texas A&M Univ, Coll Med, Dept Translat Med Sci, Houston, TX 77030 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 16期

基金：

美国国家卫生研究院;

关键词：

RESPIRATORY SYNDROME; CORONAVIRUS; DISCOVERY;

D O I：

10.1021/acs.jmedchem.3c00221

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SARS-CoV-2, the COVID-19 pathogen, relies on its mainprotease(M-Pro) for replication and pathogenesis. M-Pro is a demonstrated target for the development of antivirals for SARS-CoV-2.Past studies have systematically explored tripeptidyl inhibitors suchas nirmatrelvir as M-Pro inhibitors. However, dipeptidylinhibitors especially those with a spiro residue at their P2 positionhave not been systematically investigated. In this work, we synthesizedabout 30 dipeptidyl M-Pro inhibitors and characterized themon enzymatic inhibition potency, structures of their complexes withM(Pro), cellular M-Pro inhibition potency, antiviralpotency, cytotoxicity, and in vitro metabolic stability.Our results indicated that M-Pro has a flexible S2 pocketto accommodate inhibitors with a large P2 residue and revealed thatdipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro [4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics.One compound, MPI60, containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylatedisplayed high antiviral potency, low cellular cytotoxicity, and high in vitro metabolic stability.

引用

页码：11040 / 11055

页数：16

共 42 条

[1] A systematic exploration of boceprevir-based main protease inhibitors as SARS-CoV-2 antivirals
Alugubelli, Yugendar R.
Geng, Zhi Zachary
Yang, Kai S.
Shaabani, Namir
Khatua, Kaustav
Ma, Xinyu R.
Vatansever, Erol C.
Cho, Chia-Chuan
Ma, Yuying
Xiao, Jing
Blankenship, Lauren R.
Yu, Ge
Sankaran, Banumathi
Li, Pingwei
Allen, Robert
Ji, Henry
Xu, Shiqing
Liu, Wenshe Ray
[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2022, 240
[2] Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial
Aman, Jurjan
Duijvelaar, Erik
Botros, Liza
Kianzad, Azar
Schippers, Job R.
Smeele, Patrick J.
Azhang, Sara
Bartelink, Imke H.
Bayoumy, Ahmed A.
Bet, Pierre M.
Boersma, Wim
Bonta, Peter, I
Boomars, Karin A. T.
Bos, Lieuwe D. J.
Bragt, Job J. M. H. van
Braunstahl, Gert-Jan
Celant, Lucas R.
Eger, Katrien A. B.
Geelhoed, J. J. Miranda
Glabbeek, Yurika L. E. van
Grotjohan, Hans P.
Hagens, Laura A.
Happe, Chris M.
Hazes, Boaz D.
Heunks, Leo M. A.
Heuvel, Michel van den
Hoefsloot, Wouter
Hoek, Rianne J. A.
Hoekstra, Romke
Hofstee, Herman M. A.
Juffermans, Nicole P.
Kemper, E. Marleen
Kos, Renate
Kunst, Peter W. A.
Lammers, Ariana
Lee, Ivo van der
Lee, E. Laurien van der
Zee, Anke-Hilse Maitland-van der
Asam, Pearl F. M. Mau
Mieras, Adinda
Muller, Mirte
Neefjes, Elisabeth C. W.
Nossent, Esther J.
Oswald, Laurien M. A.
Overbeek, Maria J.
Pamplona, Carolina C.
Paternotte, Nienke
Pronk, Niels
Raaf, Michiel A. de
Raaij, Bas F. M. van
[J]. LANCET RESPIRATORY MEDICINE, 2021, 9 (09) : 957 - 968
[3] Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors
Bai, Bing
Arutyunova, Elena
Khan, Muhammad Bashir
Lu, Jimmy
Joyce, Michael A.
Saffran, Holly A.
Shields, Justin A.
Kandadai, Appan Srinivas
Belovodskiy, Alexandr
Hena, Mostofa
Vuong, Wayne
Lamer, Tess
Young, Howard S.
Vederas, John C.
Tyrrell, D. Lorne
Lemieux, M. Joanne
Nieman, James A.
[J]. RSC MEDICINAL CHEMISTRY, 2021, 12 (10): : 1722 - 1730
[4] Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability
Bai, Bing
Belovodskiy, Alexandr
Hena, Mostofa
Kandadai, Appan Srinivas
Joyce, Michael A.
Saffran, Holly A.
Shields, Justin A.
Khan, Muhammad Bashir
Arutyunova, Elena
Lu, Jimmy
Bajwa, Sardeev K.
Hockman, Darren
Fischer, Conrad
Lamer, Tess
Vuong, Wayne
van Belkum, Marco J.
Gu, Zhengxian
Lin, Fusen
Du, Yanhua
Xu, Jia
Rahim, Mohammad
Young, Howard S.
Vederas, John C.
Tyrrell, D. Lorne
Lemieux, M. Joanne
Nieman, James A.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (04) : 2905 - 2925
[5] Remdesivir for the Treatment of Covid-19-Final Report
Beigel, John H.
Tomashek, Kay M.
Dodd, Lori E.
Mehta, Aneesh K.
Zingman, Barry S.
Kalil, Andre C.
Hohmann, Elizabeth
Chu, Helen Y.
Luetkemeyer, Annie
Kline, Susan
de Castilla, Diego Lopez
Finberg, Robert W.
Dierberg, Kerry
Tapson, Victor
Hsieh, Lanny
Patterson, Thomas F.
Paredes, Roger
Sweeney, Daniel A.
Short, William R.
Touloumi, Giota
Lye, David Chien
Ohmagari, Norio
Oh, Myoung-don
Ruiz-Palacios, Guillermo M.
Benfield, Thomas
Faetkenheuer, Gerd
Kortepeter, Mark G.
Atmar, Robert L.
Creech, C. Buddy
Lundgren, Jens
Babiker, Abdel G.
Pett, Sarah
Neaton, James D.
Burgess, Timothy H.
Bonnett, Tyler
Green, Michelle
Makowski, Mat
Osinusi, Anu
Nayak, Seema
Lane, H. Clifford
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (19) : 1813 - 1826
[6] Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients
Bernal, A. Jayk
da Silva, M. M. Gomes
Musungaie, D. B.
Kovalchuk, E.
Gonzalez, A.
Delos Reyes, V
Martin-Quiros, A.
Caraco, Y.
Williams-Diaz, A.
Brown, M. L.
Du, J.
Pedley, A.
Assaid, C.
Strizki, J.
Grobler, J. A.
Shamsuddin, H. H.
Tipping, R.
Wan, H.
Paschke, A.
Butterton, J. R.
Johnson, M. G.
De Anda, C.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2022, 386 (06) : 509 - 520
[7] Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
Boras, Britton
Jones, Rhys M.
Anson, Brandon J.
Arenson, Dan
Aschenbrenner, Lisa
Bakowski, Malina A.
Beutler, Nathan
Binder, Joseph
Chen, Emily
Eng, Heather
Hammond, Holly
Hammond, Jennifer
Haupt, Robert E.
Hoffman, Robert
Kadar, Eugene P.
Kania, Rob
Kimoto, Emi
Kirkpatrick, Melanie G.
Lanyon, Lorraine
Lendy, Emma K.
Lillis, Jonathan R.
Logue, James
Luthra, Suman A.
Ma, Chunlong
Mason, Stephen W.
McGrath, Marisa E.
Noell, Stephen
Obach, R. Scott
O' Brien, Matthew N.
O'Connor, Rebecca
Ogilvie, Kevin
Owen, Dafydd
Pettersson, Martin
Reese, Matthew R.
Rogers, Thomas F.
Rosales, Romel
Rossulek, Michelle I.
Sathish, Jean G.
Shirai, Norimitsu
Steppan, Claire
Ticehurst, Martyn
Updyke, Lawrence W.
Weston, Stuart
Zhu, Yuao
White, Kris M.
Garcia-Sastre, Adolfo
Wang, Jun
Chatterjee, Arnab K.
Mesecar, Andrew D.
Frieman, Matthew B.
[J]. NATURE COMMUNICATIONS, 2021, 12 (01)
[8] Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay
Cao, Wenyue
Cho, Chia-Chuan Dean
Geng, Zhi Zachary
Shaabani, Namir
Ma, Xinyu R.
Vatansever, Erol C.
Alugubelli, Yugendar R.
Ma, Yuying
Chaki, Sankar P.
Ellenburg, William H.
Yang, Kai S.
Qiao, Yuchen
Allen, Robert
Neuman, Benjamin W.
Ji, Henry
Xu, Shiqing
Liu, Wenshe Ray
[J]. ACS CENTRAL SCIENCE, 2022, 8 (02) : 192 - 204
[9] Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects
Cheng, Ya-Wen
Chao, Tai-Ling
Li, Chiao-Ling
Chiu, Mu-Fan
Kao, Han-Chieh
Wang, Sheng-Han
Pang, Yu-Hao
Lin, Chih-Hui
Tsai, Ya-Min
Lee, Wen-Hau
Tao, Mi-Hua
Ho, Tung-Ching
Wu, Ping-Yi
Jang, Li-Ting
Chen, Pei-Jer
Chang, Sui-Yuan
Yeh, Shiou-Hwei
[J]. CELL REPORTS, 2020, 33 (02):
[10] Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2
Dai, Wenhao
Jochmans, Dirk
Xie, Hang
Yang, Hang
Li, Jian
Su, Haixia
Chang, Di
Wang, Jiang
Peng, Jingjing
Zhu, Lili
Nian, Yong
Hilgenfeld, Rolf
Jiang, Hualiang
Chen, Kaixian
Zhang, Leike
Xu, Yechun
Neyts, Johan
Liu, Hong
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (04) : 2794 - 2808

← 1 2 3 4 5 →