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Molecules
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Design, Synthesis, and Evaluation of Protease Inhibitors
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Design, Synthesis, and Evaluation of Protease Inhibitors

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 5491

Special Issue Editors

Dr. Zhengnian Li

E-Mail Website
Guest Editor
Stanford Cancer Institute, Stanford, CA, USA
Interests: developing of small-molecule inhibitors; developing bifunctional small molecules
Prof. Dr. Nikolay Danchev

E-Mail Website
Guest Editor
Department of Pharmacology, Pharmacotherapy and Toxicology, Medical University of Sofia, Sofia, Bulgaria
Interests: drug toxicology and drug metabolism; pharmacokinetics

Special Issue Information

Dear Colleagues,

Proteases are complexes of enzymes that break the peptide bonds of proteins; they are divided into their individual components. Proteases can be obtained from all forms of life and viruses. Proteases are crucial for protein synthesis, turnover, and regulate many cellular processes, such as gene expression, differentiation, migration, immunological defense, apoptosis, and cell death. Inhibitors of proteases are emerging with promising therapeutic uses in the treatment of many diseases such as cancers, fungal and viral infections, and inflammatory, immunological, and respiratory diseases. This Special Issue focuses on the design, synthesis, and evaluation of protease inhibitors.

We welcome all types of manuscripts, including research articles, review articles, and translational research on the development of protease inhibitors in multiple areas.

Dr. Zhengnian Li
Prof. Dr. Nikolay Danchev
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protease
  • protease inhibitors
  • organic synthesis
  • cancer
  • viral infections
  • drug design
  • medicinal chemistry

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Published Papers (3 papers)

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Research

14 pages, 3098 KiB  
Article
Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase
by Karolina Torzyk-Jurowska, Jaroslaw Ciekot and Lukasz Winiarski
Molecules 2024, 29(5), 1120; https://doi.org/10.3390/molecules29051120 - 1 Mar 2024
Viewed by 1179
Abstract
Despite many years of research, human neutrophil elastase (HNE) still remains an area of interest for many researchers. This multifunctional representative of neutrophil serine proteases is one of the most destructive enzymes found in the human body which can degrade most of the [...] Read more.
Despite many years of research, human neutrophil elastase (HNE) still remains an area of interest for many researchers. This multifunctional representative of neutrophil serine proteases is one of the most destructive enzymes found in the human body which can degrade most of the extracellular matrix. Overexpression or dysregulation of HNE may lead to the development of several inflammatory diseases. Previously, we presented the HNE inhibitor with kinact/KI value over 2,000,000 [M−1s−1]. In order to optimize its structure, over 100 novel tripeptidyl derivatives of α-aminoalkylphosphonate diaryl esters were synthesized, and their activity toward HNE was checked. To confirm the selectivity of the resultant compounds, several of the most active were additionally checked against the two other neutrophil proteases: proteinase 3 and cathepsin G. The developed modifications allowed us to obtain a compound with significantly increased inhibitory activity against human neutrophil elastase with high selectivity toward cathepsin G, but none toward proteinase 3. Full article
(This article belongs to the Special Issue Design, Synthesis, and Evaluation of Protease Inhibitors)
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17 pages, 3021 KiB  
Article
Development of FRET and Stress Granule Dual-Based System to Screen for Viral 3C Protease Inhibitors
by Jingjing Zhang, Yingpei Jiang, Chunxiu Wu, Dan Zhou, Jufang Gong, Tiejun Zhao and Zhigang Jin
Molecules 2023, 28(7), 3020; https://doi.org/10.3390/molecules28073020 - 28 Mar 2023
Cited by 4 | Viewed by 2109
Abstract
3C proteases (3Cpros) of picornaviruses and 3C-like proteases (3CLpros) of coronaviruses and caliciviruses represent a group of structurally and functionally related viral proteases that play pleiotropic roles in supporting the viral life cycle and subverting host antiviral responses. The design and screening for [...] Read more.
3C proteases (3Cpros) of picornaviruses and 3C-like proteases (3CLpros) of coronaviruses and caliciviruses represent a group of structurally and functionally related viral proteases that play pleiotropic roles in supporting the viral life cycle and subverting host antiviral responses. The design and screening for 3C/3CLpro inhibitors may contribute to the development broad-spectrum antiviral therapeutics against viral diseases related to these three families. However, current screening strategies cannot simultaneously assess a compound’s cytotoxicity and its impact on enzymatic activity and protease-mediated physiological processes. The viral induction of stress granules (SGs) in host cells acts as an important antiviral stress response by blocking viral translation and stimulating the host immune response. Most of these viruses have evolved 3C/3CLpro-mediated cleavage of SG core protein G3BP1 to counteract SG formation and disrupt the host defense. Yet, there are no SG-based strategies screening for 3C/3CLpro inhibitors. Here, we developed a fluorescence resonance energy transfer (FRET) and SG dual-based system to screen for 3C/3CLpro inhibitors in living cells. We took advantage of FRET to evaluate the protease activity of poliovirus (PV) 3Cpro and live-monitor cellular SG dynamics to cross-verify its effect on the host antiviral response. Our drug screen uncovered a novel role of Telaprevir and Trifluridine as inhibitors of PV 3Cpro. Moreover, Telaprevir and Trifluridine also modulated 3Cpro-mediated physiological processes, including the cleavage of host proteins, inhibition of the innate immune response, and consequent facilitation of viral replication. Taken together, the FRET and SG dual-based system exhibits a promising potential in the screening for inhibitors of viral proteases that cleave G3BP1. Full article
(This article belongs to the Special Issue Design, Synthesis, and Evaluation of Protease Inhibitors)
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20 pages, 7184 KiB  
Article
Amino Acid Substitutions at P1 Position Change the Inhibitory Activity and Specificity of Protease Inhibitors BmSPI38 and BmSPI39 from Bombyx mori
by Youshan Li, Meng Wei, Jie Zhang, Rui Zhu, Yuan Wang, Zhaofeng Zhang, Changqing Chen and Ping Zhao
Molecules 2023, 28(5), 2073; https://doi.org/10.3390/molecules28052073 - 22 Feb 2023
Cited by 1 | Viewed by 1836
Abstract
It was found that silkworm serine protease inhibitors BmSPI38 and BmSPI39 were very different from typical TIL-type protease inhibitors in sequence, structure, and activity. BmSPI38 and BmSPI39 with unique structure and activity may be good models for studying the relationship between the structure [...] Read more.
It was found that silkworm serine protease inhibitors BmSPI38 and BmSPI39 were very different from typical TIL-type protease inhibitors in sequence, structure, and activity. BmSPI38 and BmSPI39 with unique structure and activity may be good models for studying the relationship between the structure and function of small-molecule TIL-type protease inhibitors. In this study, site-directed saturation mutagenesis at the P1 position was conducted to investigate the effect of P1 sites on the inhibitory activity and specificity of BmSPI38 and BmSPI39. In-gel activity staining and protease inhibition experiments confirmed that BmSPI38 and BmSPI39 could strongly inhibit elastase activity. Almost all mutant proteins of BmSPI38 and BmSPI39 retained the inhibitory activities against subtilisin and elastase, but the replacement of P1 residues greatly affected their intrinsic inhibitory activities. Overall, the substitution of Gly54 in BmSPI38 and Ala56 in BmSPI39 with Gln, Ser, or Thr was able to significantly enhance their inhibitory activities against subtilisin and elastase. However, replacing P1 residues in BmSPI38 and BmSPI39 with Ile, Trp, Pro, or Val could seriously weaken their inhibitory activity against subtilisin and elastase. The replacement of P1 residues with Arg or Lys not only reduced the intrinsic activities of BmSPI38 and BmSPI39, but also resulted in the acquisition of stronger trypsin inhibitory activities and weaker chymotrypsin inhibitory activities. The activity staining results showed that BmSPI38(G54K), BmSPI39(A56R), and BmSPI39(A56K) had extremely high acid–base and thermal stability. In conclusion, this study not only confirmed that BmSPI38 and BmSPI39 had strong elastase inhibitory activity, but also confirmed that P1 residue replacement could change their activity and inhibitory specificity. This not only provides a new perspective and idea for the exploitation and utilization of BmSPI38 and BmSPI39 in biomedicine and pest control, but also provides a basis or reference for the activity and specificity modification of TIL-type protease inhibitors. Full article
(This article belongs to the Special Issue Design, Synthesis, and Evaluation of Protease Inhibitors)
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