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Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 7419

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Dr. Roberta Ettari

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Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
Interests: peptide-based inhibitors; peptidomimetics; bioactive inhibitors; cysteine proteases; proteasome; anticancer; inhibitors from nature; drug-combination studies
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Special Issue Information

Dear Colleagues,

Proteases are one of the largest and most important groups of enzymes. They selectively catalyze the hydrolysis of peptide bonds and can be divided into five main classes: cysteine, serine, threonine, aspartic and metallo-proteases.

Proteases are involved in a number of relevant physiological processes, including protein turnover, digestion, cell differentiation and growth, immune response and apoptosis.

Uncontrolled or undesired proteolysis can lead to many pathological states, including cancer, inflammatory, autoimmune or neurodegenerative diseases.

At the same time, several proteases play a crucial role in the virus, protozoa and bacteria lifecycles; thus, they are recognized as ideal targets for the design of novel effective agents for the treatment of infectious diseases.

In this Special Issue, we aim to provide evidence for the most innovative targets that scientists have identified to develop novel protease inhibitors endowed with strong therapeutic potential.

Prof. Dr. Roberta Ettari
Guest Editor

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Keywords

cysteine proteases
serine proteases
threonine proteases
aspartic proteases
metallo-proteases
infectious diseases
cancer
inflammatory diseases
neurodegenerative disease
autoimmune diseases

Published Papers (6 papers)

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Editorial

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4 pages, 205 KiB

Open AccessEditorial

Cysteine Proteases as Validated Targets for the Treatment of Neglected and Poverty-Related Parasitic Diseases

by Roberta Ettari

Int. J. Mol. Sci. 2023, 24(12), 10097; https://doi.org/10.3390/ijms241210097 - 13 Jun 2023

Viewed by 758

Abstract

Neglected tropical diseases (NTDs) include 20 diverse infections mainly prevalent in tropical areas that mostly affect disadvantaged communities and women and children [...] Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

Research

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15 pages, 6292 KiB

Open AccessArticle

Blunting Neuroinflammation by Targeting the Immunoproteasome with Novel Amide Derivatives

by Chiara Imbesi, Roberta Ettari, Natasha Irrera, Maria Zappalà, Giovanni Pallio, Alessandra Bitto and Federica Mannino

Int. J. Mol. Sci. 2023, 24(13), 10732; https://doi.org/10.3390/ijms241310732 - 27 Jun 2023

Cited by 1 | Viewed by 916

Abstract

Neuroinflammation is an inflammatory response of the nervous tissue mediated by the production of cytokines, chemokines, and reactive oxygen species. Recent studies have shown that an upregulation of immunoproteasome is highly associated with various diseases and its inhibition attenuates neuroinflammation. In this context, the development of non-covalent immunoproteasome-selective inhibitors could represent a promising strategy for treating inflammatory diseases. Novel amide derivatives, KJ3 and KJ9, inhibit the β5 subunit of immunoproteasome and were used to evaluate their possible anti-inflammatory effects in an in vitro model of TNF-α induced neuroinflammation. Differentiated SH-SY5Y and microglial cells were challenged with 10 ng/mL TNF-α for 24 h and treated with KJ3 (1 µM) and KJ9 (1 µM) for 24 h. The amide derivatives showed a significant reduction of oxidative stress and the inflammatory cascade triggered by TNF-α reducing p-ERK expression in treated cells. Moreover, the key action of these compounds on the immunoproteasome was further confirmed by halting the IkB-α phosphorylation and the consequent inhibition of NF-kB. As downstream targets, IL-1β and IL-6 expression resulted also blunted by either KJ3 and KJ9. These preliminary results suggest that the effects of these two compounds during neuroinflammatory response relies on the reduced expression of pro-inflammatory targets. Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

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18 pages, 16663 KiB

Open AccessArticle

Virtual Screening Strategy and In Vitro Tests to Identify New Inhibitors of the Immunoproteasome

by Giulia Culletta, Marco Tutone, Roberta Ettari, Ugo Perricone, Carla Di Chio, Anna Maria Almerico and Maria Zappalà

Int. J. Mol. Sci. 2023, 24(13), 10504; https://doi.org/10.3390/ijms241310504 - 22 Jun 2023

Viewed by 809

Abstract

Immunoproteasome inhibition is a promising strategy for the treatment of hematological malignancies, autoimmune diseases, and inflammatory diseases. The design of non-covalent inhibitors of the immunoproteasome β1i/β5i catalytic subunits could be a novel approach to avoid the drawbacks of the known covalent inhibitors, such as toxicity due to off-target binding. In this work, we report the biological evaluation of thirty-four compounds selected from a commercially available collection. These hit compounds are the outcomes of a virtual screening strategy including a dynamic pharmacophore modeling approach onto the β1i subunit and a pharmacophore/docking approach onto the β5i subunit. The computational studies were first followed by in vitro enzymatic assays at 100 μM. Only compounds capable of inhibiting the enzymatic activity by more than 50% were characterized in detail using Tian continuous assays, determining the dissociation constant (K_i) of the non-covalent complex where K_i is also the measure of the binding affinity. Seven out of thirty-four hits showed to inhibit β1i and/or β5i subunit. Compound 3 is the most active on the β1i subunit with K_i = 11.84 ± 1.63 µM, and compound 17 showed K_i = 12.50 ± 0.77 µM on the β5i subunit. Compound 2 showed inhibitory activity on both subunits (K_i = 12.53 ± 0.18 and K_i = 31.95 ± 0.81 on the β1i subunit and β5i subunit, respectively). The induced fit docking analysis revealed interactions with Thr1 and Phe31 of β1i subunit and that represent new key residues as reported in our previous work. Onto β5i subunit, it interacts with the key residues Thr1, Thr21, and Tyr169. This last hit compound identified represents an interesting starting point for further optimization of β1i/β5i dual inhibitors of the immunoproteasome. Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

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11 pages, 1971 KiB

Open AccessArticle

Dipeptide Nitrile CD34 with Curcumin: A New Improved Combination Strategy to Synergistically Inhibit Rhodesain of Trypanosoma brucei rhodesiense

by Carla Di Chio, Santo Previti, Noemi Totaro, Fabiola De Luca, Alessandro Allegra, Tanja Schirmeister, Maria Zappalà and Roberta Ettari

Int. J. Mol. Sci. 2023, 24(10), 8477; https://doi.org/10.3390/ijms24108477 - 09 May 2023

Viewed by 984

Abstract

Rhodesain is the main cysteine protease of Trypanosoma brucei rhodesiense, the parasite causing the acute lethal form of Human African Trypanosomiasis. Starting from the dipeptide nitrile CD24, the further introduction of a fluorine atom in the meta position of the phenyl ring spanning in the P3 site and the switch of the P2 leucine with a phenylalanine led to CD34, a synthetic inhibitor that shows a nanomolar binding affinity towards rhodesain (K_i = 27 nM) and an improved target selectivity with respect to the parent dipeptide nitrile CD24. In the present work, following the Chou and Talalay method, we carried out a combination study of CD34 with curcumin, a nutraceutical obtained from Curcuma longa L. Starting from an affected fraction (f_a) of rhodesain inhibition of 0.5 (i.e., the IC₅₀), we observed an initial moderate synergistic action, which became a synergism for f_a values ranging from 0.6 to 0.7 (i.e., 60–70% inhibition of the trypanosomal protease). Interestingly, at 80–90% inhibition of rhodesain proteolytic activity, we observed a strong synergism, resulting in 100% enzyme inhibition. Overall, in addition to the improved target selectivity of CD34 with respect to CD24, the combination of CD34 + curcumin resulted in an increased synergistic action with respect to CD24 + curcumin, thus suggesting that it is desirable to use CD34 and curcumin in combination. Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

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29 pages, 5998 KiB

Open AccessArticle

Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study

by Patrick Müller, Mergim Meta, Jan Laurenz Meidner, Marvin Schwickert, Jessica Meyr, Kevin Schwickert, Christian Kersten, Collin Zimmer, Stefan Josef Hammerschmidt, Ariane Frey, Albin Lahu, Sergio de la Hoz-Rodríguez, Laura Agost-Beltrán, Santiago Rodríguez, Kira Diemer, Wilhelm Neumann, Florenci V. Gonzàlez, Bernd Engels and Tanja Schirmeister

Int. J. Mol. Sci. 2023, 24(8), 7226; https://doi.org/10.3390/ijms24087226 - 13 Apr 2023

Cited by 3 | Viewed by 2249

Abstract

Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences suited for five different proteases were investigated, highlighting the impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity. Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum mechanics simulations. Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

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9 pages, 1686 KiB

Open AccessArticle

Drug Combination Studies of the Dipeptide Nitrile CD24 with Curcumin: A New Strategy to Synergistically Inhibit Rhodesain of Trypanosoma brucei rhodesiense

by Carla Di Chio, Santo Previti, Fabiola De Luca, Marta Bogacz, Collin Zimmer, Annika Wagner, Tanja Schirmeister, Maria Zappalà and Roberta Ettari

Int. J. Mol. Sci. 2022, 23(22), 14470; https://doi.org/10.3390/ijms232214470 - 21 Nov 2022

Cited by 2 | Viewed by 1174

Abstract

Rhodesain is a cysteine protease that is crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite causing the lethal form of Human African Trypanosomiasis. CD24 is a recently developed synthetic inhibitor of rhodesain, characterized by a nanomolar affinity towards the trypanosomal protease (K_i = 16 nM), and acting as a competitive inhibitor. In the present work, we carried out a combination study of CD24 with curcumin, the multitarget nutraceutical obtained from Curcuma longa L., which we demonstrated to inhibit rhodesain in a non-competitive manner. By applying the Chou and Talalay method, we obtained an initial additive effect at IC₅₀ (f_a = 0.5, Combination Index = 1), while for the most relevant f_a values, ranging from 0.6 to 1, i.e., from 60% to 100% of rhodesain inhibition, we obtained a combination index < 1, thus suggesting that an increasingly synergistic action occurred for the combination of the synthetic inhibitor CD24 and curcumin. Furthermore, the combination of the two inhibitors showed an antitrypanosomal activity better than that of CD24 alone (EC₅₀ = 4.85 µM and 10.1 µM for the combination and CD24, respectively), thus suggesting the use of the two inhibitors in combination is desirable. Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

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