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Molecules
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Covalent Inhibitors in Drug Discovery and Chemical Biology
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Covalent Inhibitors in Drug Discovery and Chemical Biology

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 16005

Special Issue Editors

Prof. Dr. Rui F. A. Moreira

E-Mail Website
Guest Editor
Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
Interests: medicinal chemistry; design of enzyme inhibitors; activity-based protein profiling; infectious diseases; cancer
Dr. Ana Sofia M. Ressurreição

E-Mail Website
Guest Editor
Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
Interests: medicinal chemistry; drug design; drug-target protein profiling; infectious diseases; cancer

Special Issue Information

Dear Colleagues,

In recent years, covalent inhibitors have reemerged not only as useful chemical tools to study biological processes but also as therapeutic tools with clinical and regulatory validation. The unique reactivity of cysteine towards electrophilic warheads has made this residue the nucleophile of choice for covalent engagement with a protein of interest. While targeting cysteine residues with covalent inhibitors has afforded numerous successful case studies, the paucity of cysteine in the proteome limits the number of proteins that can be targeted by this approach. This drawback has led to the development of novel methodologies that include targeted covalent inhibitors (TCIs) designed to bind poorly conserved amino acids for covalent modification. With this Special Issue, we will provide the scientific community with a survey on the current advances in novel strategies and warheads that covalently modify different nucleophilic amino acids in proteins, and how these findings have been translated into new therapeutic solutions for specific unmet medical needs. Issues of utmost importance in designing efficacious and safe covalent inhibitors, such as modulation of the duration of action and management of toxicity risks, will also be addressed. Finally, we will include recent breakthroughs in activity-based protein profiling (ABPP), which has greatly expanded the proteome coverage using probes that exploit specific reactivity and/or structural features of active sites to achieve the covalent labeling of proteins.

Prof. Dr. Rui F. A. Moreira
Dr. Ana Sofia M. Ressurreição
Guest Editors

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Keywords

  • Targeted covalent inhibitors
  • Mechanism-based drugs
  • Warhead reactivity
  • Activity-based protein profiling
  • Drug design
  • Protein modification

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Published Papers (3 papers)

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Research

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22 pages, 9886 KiB  
Article
Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases—Studies on Inhibition Mechanism and Kinetics
by Philipp Klein, Fabian Barthels, Patrick Johe, Annika Wagner, Stefan Tenzer, Ute Distler, Thien Anh Le, Paul Schmid, Volker Engel, Bernd Engels, Ute A. Hellmich, Till Opatz and Tanja Schirmeister
Molecules 2020, 25(9), 2064; https://doi.org/10.3390/molecules25092064 - 28 Apr 2020
Cited by 26 | Viewed by 4249
Abstract
The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the [...] Read more.
The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action. Full article
(This article belongs to the Special Issue Covalent Inhibitors in Drug Discovery and Chemical Biology)
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22 pages, 5903 KiB  
Article
New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain
by Philipp Klein, Patrick Johe, Annika Wagner, Sascha Jung, Jonas Kühlborn, Fabian Barthels, Stefan Tenzer, Ute Distler, Waldemar Waigel, Bernd Engels, Ute A. Hellmich, Till Opatz and Tanja Schirmeister
Molecules 2020, 25(6), 1451; https://doi.org/10.3390/molecules25061451 - 23 Mar 2020
Cited by 18 | Viewed by 5356
Abstract
Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of [...] Read more.
Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (Ki = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the SNAr reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation. Full article
(This article belongs to the Special Issue Covalent Inhibitors in Drug Discovery and Chemical Biology)
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Review

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14 pages, 3940 KiB  
Review
Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases
by Simone Brogi, Roberta Ibba, Sara Rossi, Stefania Butini, Vincenzo Calderone, Sandra Gemma and Giuseppe Campiani
Molecules 2022, 27(8), 2561; https://doi.org/10.3390/molecules27082561 - 15 Apr 2022
Cited by 23 | Viewed by 5344
Abstract
In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main [...] Read more.
In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue. Full article
(This article belongs to the Special Issue Covalent Inhibitors in Drug Discovery and Chemical Biology)
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