Nitriles: an attractive approach to the development of covalent inhibitors

Vinícius Bonatto, Rafael F. Lameiro, Fernanda R. Rocho, Jerônimo Lameira, Andrei Leitão and Carlos A. Montanari

RSC Med. Chem., 2023, 14, 201
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On the origins of SARS-CoV-2 main protease inhibitors

Yves L. Janin

RSC Med. Chem., 2024, 15, 81
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Sustainable and Chemoselective Synthesis of α-Aminonitriles Using Lewis and Brønsted Acid-Functionalized Nanoconfined Spaces

Chloe A. Ramsperger, Noah Q. Tufts, Ankit K. Yadav, Jacob M. Lessard and Kyriakos C. Stylianou

ACS Appl. Mater. Interfaces, 2022, 14, 49957
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Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine

Lennart Brewitz, Leo Dumjahn, Yilin Zhao, C. David Owen, Stephen M. Laidlaw, Tika R. Malla, Dung Nguyen, Petra Lukacik, Eidarus Salah, Adam D. Crawshaw, Anna J. Warren, Jose Trincao, Claire Strain-Damerell, Miles W. Carroll, Martin A. Walsh and Christopher J. Schofield

J. Med. Chem., 2023, 66, 2663
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Synthesis, molecular docking, and binding Gibbs free energy calculation of β-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease

Ze-jun Jia, Xiao-wei Lan, Kui Lu, Xuan Meng, Wen-jie Jing, Shi-ru Jia, Kai Zhao and Yu-jie Dai

Journal of Molecular Structure, 2023, 1284, 135409
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Inhibition of dimeric SARS-CoV-2 Mpro displays positive cooperativity and a mixture of covalent and non-covalent binding

Krishna M. Padmanabha Das, Jun Chen, Paul S. Charifson, Jeremy Green, Henry Tang, Sanjay Panchal, Fan Pu, Alla Korepanova, Abhinav Dubey, Gustavo Afanador, Vladimir Stojkovic, Boguslaw Nocek, Lance Bigelow, Sarah H. Stubbs, Robert A. Davey, David A. DeGoey, Haribabu Arthanari and Mark N. Namchuk

iScience, 2025, 28, 112773
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Development of 2-chloroquinoline based heterocyclic frameworks as dual inhibitors of SARS-CoV-2 MPro and PLPro

Bhavita Kattula, Bharati Reddi, Aruna Jangam, Lekhika Naik, Bala Manikanta Adimoolam, Suresh Vavilapalli, Sayanna Are, Jagadeshwar Reddy Thota, Surender Singh Jadav, Mohammed Arifuddin and Anthony Addlagatta

International Journal of Biological Macromolecules, 2023, 242, 124772
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Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review

Xin Li and Yongcheng Song

European Journal of Medicinal Chemistry, 2023, 260, 115772
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A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease

Zhi Zachary Geng, Sandeep Atla, Namir Shaabani, Veerabhadra Vulupala, Kai S. Yang, Yugendar R. Alugubelli, Kaustav Khatua, Peng-Hsun Chen, Jing Xiao, Lauren R. Blankenship, Xinyu R. Ma, Erol C. Vatansever, Chia-Chuan D. Cho, Yuying Ma, Robert Allen, Henry Ji, Shiqing Xu and Wenshe Ray Liu

J. Med. Chem., 2023, 66, 11040
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Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease

Yuya Hirose, Naoya Shindo, Makiko Mori, Satsuki Onitsuka, Hikaru Isogai, Rui Hamada, Tadanari Hiramoto, Jinta Ochi, Daisuke Takahashi, Tadashi Ueda, Jose M. M. Caaveiro, Yuya Yoshida, Shigehiro Ohdo, Naoya Matsunaga, Shinsuke Toba, Michihito Sasaki, Yasuko Orba, Hirofumi Sawa, Akihiko Sato, Eiji Kawanishi and Akio Ojida

J. Med. Chem., 2022, 65, 13852
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The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism

Elena Arutyunova, Alexandr Belovodskiy, Pu Chen, Muhammad Bashir Khan, Michael Joyce, Holly Saffran, Jimmy Lu, Zoe Turner, Bing Bai, Tess Lamer, Howard S. Young, John C. Vederas, D. Lorne Tyrrell, M. Joanne Lemieux and James A. Nieman

ACS Bio Med Chem Au, 2023, 3, 528
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A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV

Pu Chen, Tayla J. Van Oers, Elena Arutyunova, Conrad Fischer, Chaoxiang Wang, Tess Lamer, Marco J. van Belkum, Howard S. Young, John C. Vederas and M. Joanne Lemieux

JACS Au, 2024, 4, 3217
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An update on the discovery and development of reversible covalent inhibitors

Faridoon, Raymond Ng, Guiping Zhang and Jie Jack Li

Med Chem Res, 2023, 32, 1039
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Dimerization Tendency of 3CLpros of Human Coronaviruses Based on the X-ray Crystal Structure of the Catalytic Domain of SARS-CoV-2 3CLpro

Seri Jo, Hwa Young Kim, Dong Hae Shin and Mi-Sun Kim

IJMS, 2022, 23, 5268
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A Novel Y-Shaped, S–O–N–O–S-Bridged Cross-Link between Three Residues C22, C44, and K61 Is Frequently Observed in the SARS-CoV-2 Main Protease

Kai S. Yang, Lauren R. Blankenship, Syuan-Ting Alex Kuo, Yan J. Sheng, Pingwei Li, Carol A. Fierke, David H. Russell, Xin Yan, Shiqing Xu and Wenshe Ray Liu

ACS Chem. Biol., 2023, 18, 449
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Structural biology of SARS-CoV-2 Mpro and drug discovery

Yinkai Duan, Haofeng Wang, Zhenghong Yuan and Haitao Yang

Current Opinion in Structural Biology, 2023, 82, 102667
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Exploring covalent inhibitors of SARS-CoV-2 main protease: from peptidomimetics to novel scaffolds

Noor Atatreh, Radwa E. Mahgoub and Mohammad A. Ghattas

Journal of Enzyme Inhibition and Medicinal Chemistry, 2025, 40
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Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination

Thanigaimalai Pillaiyar, Philipp Flury, Nadine Krüger, Haixia Su, Laura Schäkel, Elany Barbosa Da Silva, Olga Eppler, Thales Kronenberger, Tianqing Nie, Stephanie Luedtke, Cheila Rocha, Katharina Sylvester, Marvin R.I. Petry, James H. McKerrow, Antti Poso, Stefan Pöhlmann, Michael Gütschow, Anthony J. O’Donoghue, Yechun Xu, Christa E. Müller and Stefan A. Laufer

J. Med. Chem., 2022, 65, 9376
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The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

Qing Hu, Yuan Xiong, Guang‐Hao Zhu, Ya‐Ni Zhang, Yi‐Wen Zhang, Ping Huang and Guang‐Bo Ge

MedComm, 2022, 3
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SARS-CoV-2 Mpro Protease Variants of Concern Display Altered Viral Substrate and Cell Host Target Galectin-8 Processing but Retain Sensitivity toward Antivirals

Sizhu Amelia Chen, Elena Arutyunova, Jimmy Lu, Muhammad Bashir Khan, Wioletta Rut, Mikolaj Zmudzinski, Shima Shahbaz, Jegan Iyyathurai, Eman W. Moussa, Zoe Turner, Bing Bai, Tess Lamer, James A. Nieman, John C. Vederas, Olivier Julien, Marcin Drag, Shokrollah Elahi, Howard S. Young and M. Joanne Lemieux

ACS Cent. Sci., 2023, 9, 696
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Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives

Andrea Citarella, Alessandro Dimasi, Davide Moi, Daniele Passarella, Angela Scala, Anna Piperno and Nicola Micale

Biomolecules, 2023, 13, 1339
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The history, mechanism, and perspectives of nirmatrelvir (PF-07321332): an orally bioavailable main protease inhibitor used in combination with ritonavir to reduce COVID-19-related hospitalizations

Ryan P. Joyce, Vivian W. Hu and Jun Wang

Med Chem Res, 2022, 31, 1637
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SARS-CoV-2 genomics and impact on clinical care for COVID-19

Ramon Lorenzo-Redondo, Alexandre Machado de Sant’Anna Carvalho, Judd F Hultquist and Egon A Ozer

Journal of Antimicrobial Chemotherapy, 2023, 78, ii25
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Self-Masked Aldehyde Inhibitors of Human Cathepsin L Are Potent Anti-CoV-2 Agents

Jiyun Zhu, Linfeng Li, Aleksandra Drelich, Bala C. Chenna, Drake M. Mellott, Zane W. Taylor, Vivian Tat, Christopher Z. Garcia, Ardala Katzfuss, Chien-Te K. Tseng and Thomas D. Meek

Front. Chem., 2022, 10
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Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors

Kaustav Khatua, Yugendar R. Alugubelli, Kai S. Yang, Veerabhadra R. Vulupala, Lauren R. Blankenship, Demonta Coleman, Sandeep Atla, Sankar P. Chaki, Zhi Zachary Geng, Xinyu R. Ma, Jing Xiao, Peng-Hsun Chen, Chia-Chuan D. Cho, Shivangi Sharma, Erol C. Vatansever, Yuying Ma, Ge Yu, Benjamin W. Neuman, Shiqing Xu and Wenshe Ray Liu

Antiviral Research, 2024, 225, 105874
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Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Philipp Flury, Julian Breidenbach, Nadine Krüger, Rabea Voget, Laura Schäkel, Yaoyao Si, Vesa Krasniqi, Sara Calistri, Matthias Olfert, Katharina Sylvester, Cheila Rocha, Raphael Ditzinger, Alexander Rasch, Stefan Pöhlmann, Thales Kronenberger, Antti Poso, Katharina Rox, Stefan A. Laufer, Christa E. Müller, Michael Gütschow and Thanigaimalai Pillaiyar

ACS Pharmacol. Transl. Sci., 2024, 7, 493
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An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Michael Westberg, Yichi Su, Xinzhi Zou, Pinghan Huang, Arjun Rustagi, Jaishree Garhyan, Puja Bhavesh Patel, Daniel Fernandez, Yan Wu, Chenzhou Hao, Chieh-Wen Lo, Marwah Karim, Lin Ning, Aimee Beck, Panatda Saenkham-Huntsinger, Vivian Tat, Aleksandra Drelich, Bi-Hung Peng, Shirit Einav, Chien-Te K. Tseng, Catherine Blish and Michael Z. Lin

Sci. Transl. Med., 2024, 16
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Leveraging viral genome sequences and machine learning models for identification of potentially selective antiviral agents

Tuan Xu, Miao Xu, Qi Zhang, Catherine Z. Chen, Wei Zheng and Ruili Huang

Commun Chem, 2025, 8
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A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

Subramanyam Vankadara, Monique Danielle Dawson, Jia Yi Fong, Qin Yao Oh, Qi An Ang, Boping Liu, Hong Yun Chang, Judice Koh, Xiaoying Koh, Qian Wen Tan, Joma Joy and Cheng San Brian Chia

ACS Med. Chem. Lett., 2022, 13, 1345
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Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

Gabriele La Monica, Alessia Bono, Antonino Lauria and Annamaria Martorana

J. Med. Chem., 2022, 65, 12500
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Potent SARS-CoV-2 3C-like protease inhibitor ( +)-eupenoxide-3,6-diketone (IC50: 0.048 μM) was synthesized based on ( +)-eupenoxide; lead from ( +)-eupenoxide analogs study by endophytic fermentation

Shoji Maehara, Moeka Kumamoto, Shogo Nakajima, Yuhzo Hieda, Koichi Watashi and Toshiyuki Hata

J Nat Med, 2025, 79, 357
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Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 Mpro and Cathepsin

Miriam R.B. Porzberg, G.J. Mirjam Groenewold, Heyrhyoung Lyoo, Alexander K.M.H. Jakob, Willem H.C. Titulaer, Lorenzo Cavina, Katrien C.K. Poelaert, Marleen Zwaagstra, Cindy E.J. Dieteren, Jaap G.H. Lemmers, S. Hakim Hamdani, Bernd N.M. van Buuren, Bart Ackerschott, Johannes Platteeuw, Joey Michorius, Byron E.E. Martina, Martin C. Feiters, Daniel Gironés, Frank J.M. van Kuppeveld, Martijn J. van Hemert and Floris P.J.T. Rutjes

J. Med. Chem., 2025, 68, 10953
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Structural biology of SARS-CoV-1/SARS-CoV-2 main protease

Yunyun Gao, Johannes Kaub, Gianluca Santoni, Nicholas Pearce and Andrea Thorn

Crystallography Reviews, 2023, 29, 76
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Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors

Julia K. Stille, Jevgenijs Tjutrins, Guanyu Wang, Felipe A. Venegas, Christopher Hennecker, Andrés M. Rueda, Itai Sharon, Nicole Blaine, Caitlin E. Miron, Sharon Pinus, Anne Labarre, Jessica Plescia, Mihai Burai Patrascu, Xiaocong Zhang, Alexander S. Wahba, Danielle Vlaho, Mitchell J. Huot, T. Martin Schmeing, Anthony K. Mittermaier and Nicolas Moitessier

European Journal of Medicinal Chemistry, 2022, 229, 114046
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SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Conrad Fischer and Jenson R. Feys

Future Pharmacology, 2023, 3, 80
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Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity

Shenghua Gao, Katharina Sylvester, Letian Song, Tobias Claff, Lanlan Jing, Molly Woodson, Renato H. Weiße, Yusen Cheng, Laura Schäkel, Marvin Petry, Michael Gütschow, Anke C. Schiedel, Norbert Sträter, Dongwei Kang, Shujing Xu, Karoly Toth, John Tavis, Ann E. Tollefson, Christa E. Müller, Xinyong Liu and Peng Zhan

J. Med. Chem., 2022, 65, 13343
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Design, Synthesis, and Biological Evaluation of Peptidomimetic Tetrahydropyrrole Spirodihydroindolones as SARS-CoV-2 3CL Protease Inhibitors

Liuyan Hu, Zhi Zhao, Shujing Zhang, Lei Yang, Wenjie Cui, Tianwen Hu, Jin Suo, Haiguo Sun, Qiumeng Zhang, Leike Zhang, Weiliang Zhu, Zhijian Xu, Yumin Zhang, Xiangrui Jiang, Yan Zhang and Jingshan Shen

ACS Med. Chem. Lett., 2025, 16, 790
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Discovery of the Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19

Yuto Unoh, Keiichiro Hirai, Shota Uehara, Sho Kawashima, Haruaki Nobori, Jun Sato, Hiromitsu Shibayama, Akihiro Hori, Kenji Nakahara, Kana Kurahashi, Masayuki Takamatsu, Shiho Yamamoto, Qianhui Zhang, Miki Tanimura, Reiko Dodo, Yuki Maruyama, Hirofumi Sawa, Ryosuke Watari, Tetsuya Miyano, Teruhisa Kato, Takafumi Sato and Yuki Tachibana

J. Med. Chem., 2025
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Alkaloids and Alkaloid-Like Compounds are Potential Scaffolds of Antiviral Agents against SARS-CoV-2 (COVID-19) Virus

Prasat Kittakoop, Dhanushka Darshana, Rapeepat Sangsuwan and Chulabhorn Mahidol

HETEROCYCLES, 2022, 105, 115
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Progress of SARS‐CoV‐2 Main protease peptide‐like inhibitors

Xiaoyong Liu, Xiaoli Ren, Miao Hua, Fang Liu, Xiaoping Ren, Chaoya Sui, Qing Li, Fen Luo, Zhiyong Jiang, Ziqiao Xia, Jingxia Chen and Bing Yang

Chem Biol Drug Des, 2024, 103
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Discovery of SARS‐CoV‐2 Inhibitors Featuring Novel Histidine α‐Nitrile Motif

Nilu Vijay Gone, Mohammed Ghalib Enayathullah, Jessie Thomas, Parth Rathee, Rajeev Prabhakar, Kiran Kumar Bokara and Gangadhar J. Sanjayan

Chemistry & Biodiversity, 2023, 20
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Discovery of highly potent covalent SARS-CoV-2 3CLpro inhibitors bearing 2-sulfoxyl-1,3,4-oxadiazole scaffold for combating COVID-19

Fu-Mao Zhang, Ting Huang, Feng Wang, Gui-Shan Zhang, Donglan Liu, Jun Dai, Jian-Wei Zhang, Qing-Hua Li, Guo-Qiang Lin, Dingding Gao, Jincun Zhao and Ping Tian

European Journal of Medicinal Chemistry, 2023, 260, 115721
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Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases

Simone Brogi, Roberta Ibba, Sara Rossi, Stefania Butini, Vincenzo Calderone, Sandra Gemma and Giuseppe Campiani

Molecules, 2022, 27, 2561
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SAR based Review on Diverse Heterocyclic Compounds with Various Potential Molecular Targets in the Fight against COVID-19: A Medicinal Chemist Perspective

Anish Madan, Mansi Garg, Garvit Satija, Barkha Sharma, Mohammad Shaquiquzzaman, Mymoona Akhter, Ashif Iqubal, Mohammad Ahmed Khan, Suhel Parvez, Anwesha Das, Khursheed Ahmad Sheikh and Mohammad Mumtaz Alam

CTMC, 2023, 23, 1319
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