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Proteases and Their Inhibitors: From Biochemistry to Applications
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Proteases and Their Inhibitors: From Biochemistry to Applications

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

Deadline for manuscript submissions: closed (20 July 2026) | Viewed by 1981

Editor

Dr. Gonzalo Izaguirre

E-Mail Website
Guest Editor
College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
Interests: proteases; serpins; coagulation factors; proprotein convertases; furin; regulation of virus cell entry by proteases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteases or peptidases are a diverse family of enzymes, universally found in all domains of life, that perform peptide bond cleavage. The MEROPS database classification of proteases organizes them into families based on their evolutionary relationships, catalytic mechanisms, and active site residues. This classification currently includes over 250 families, grouped into 7 major catalytic types (serine, cysteine, aspartic, metallo, threonine, glutamic, and mixed- or unknown-mechanism proteases) and organized within approximately 60 clans. Proteases perform their function in pair with their inhibitors, sometimes forming a regulatory network. Medically relevant protease–inhibitor pairs are essential for maintaining physiological homeostasis across processes like coagulation, immune response, tissue remodeling, apoptosis, digestion, and viral replication. The dysregulation of these pairs’ functionality often leads to diseases such as cancer, inflammation, neurodegeneration, and infections. Protease–inhibitor pairs are vital for agriculture, playing roles in plant defense, stress tolerance, crop improvement, and post-harvest management. Leveraging these systems through genetic engineering and biotechnological innovations holds significant promise for sustainable agriculture and enhanced food security. Proteases and their inhibitors are indispensable in molecular sciences due to their critical roles in health, disease, environmental, and industrial applications. Understanding their mechanisms of action and functions in diverse biological systems opens pathways for innovation and advances in biotechnology.

This Special Issue aims to compile a representative and updated survey of examples, showing progress in our understanding and commercial application of proteases and their inhibitors. It invites expert-level contributions describing how proteases and their inhibitors benefit humans and the world’s economy.

Dr. Gonzalo Izaguirre
Guest Editor

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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • proteases
  • peptidases
  • proteinases
  • proteolysis
  • hydrolysis
  • enzymes
  • inhibitors
  • biotechnology
  • drug discovery
  • therapeutics

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Published Papers (2 papers)

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Research

19 pages, 3255 KB  
Article
PhageScout: Protease Cleavage Site Prediction Using an Experimental Substrate Phage Display Motif-Based Approach
by Enoch Yu, Matthew L. Holding, Rex Huang, Andrew Chan, Cherie Teney and Colin A. Kretz
Int. J. Mol. Sci. 2026, 27(17), 7593; https://doi.org/10.3390/ijms27177593 - 25 Aug 2026
Abstract
Identification of protease cleavage sites is essential for understanding biological regulation and disease mechanisms, yet many predictive approaches rely on annotated substrates and curated databases, limiting performance for poorly characterized proteases. We present PhageScout, a framework for database-independent generation of protease-specific features to [...] Read more.
Identification of protease cleavage sites is essential for understanding biological regulation and disease mechanisms, yet many predictive approaches rely on annotated substrates and curated databases, limiting performance for poorly characterized proteases. We present PhageScout, a framework for database-independent generation of protease-specific features to predict cleavage sites using de novo experimental substrate phage display screening. We screened a randomized 5-mer phage display library against two neutrophil serine proteases (cathepsin G, elastase). Cleaved peptides generated position weight matrices (PWMs) and peptide enrichment scores to evaluate cleavage-site likelihood across substrate sequences. Sequence-derived scores were integrated with structural features, including accessibility and flexibility, using XGBoost classification models. Performance was benchmarked against annotated cleavage sites from the MEROPS peptidase database as reference data. Phage-derived PWM scores alone captured protease preferences and discriminated cleavage sites from background sites. Without model fitting, PWM scores achieved an area under the curve (AUC) of 0.756 (95%CI: 0.714–0.797) (cathepsin G) and 0.787 (95%CI: 0.753–0.821) (elastase). Combining broad and specific phage-derived scores improved cathepsin G prediction (AUC = 0.783), whereas this improvement was not observed for elastase. Compared to only phage-derived features, XGBoost models integrating phage sequence and structural features provided modest gains for elastase (AUC = 0.775 to 0.806), with phage-derived features ranking among the strongest predictors, but not cathepsin G (AUC = 0.702 to 0.710). Our findings demonstrate that PhageScout can use experimentally derived cleavage signatures to generate protease-specific predictive features and prioritize protease cleavage sites, providing a framework that warrants further validation across diverse proteases and biological contexts. Full article
(This article belongs to the Special Issue Proteases and Their Inhibitors: From Biochemistry to Applications)
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20 pages, 4121 KB  
Article
The Allosteric Communication Network in the Activation of Antithrombin by Heparin
by Gonzalo Izaguirre
Int. J. Mol. Sci. 2025, 26(18), 8984; https://doi.org/10.3390/ijms26188984 - 15 Sep 2025
Cited by 1 | Viewed by 1338
Abstract
The allosteric activation of antithrombin (AT) involves a conformational shift from a native, repressed (R) to a heparin-bound, activated (AH) state. Using computational structural analysis, we identified an evolutionarily conserved allosteric communication network (ACN) comprising the residues H120, Y131, and Y166, which undergo [...] Read more.
The allosteric activation of antithrombin (AT) involves a conformational shift from a native, repressed (R) to a heparin-bound, activated (AH) state. Using computational structural analysis, we identified an evolutionarily conserved allosteric communication network (ACN) comprising the residues H120, Y131, and Y166, which undergo key structural displacements during this transition. Site-directed mutagenesis of these residues markedly enhanced AT native reactivity toward FXa and reduced thermal stability, indicating their role in stabilizing the R state. These findings support a three-step “slingshot” model in which the ACN functions as a molecular lock that restrains stored conformational energy, preventing premature activation. Heparin binding disengages this lock, triggering a cascade of structural changes that propagate from the heparin-binding site (HBS) to the reactive center loop (RCL). Additional mutational analyses of residues bridging the β-sheet A (βsA) and the RCL/exosite domains revealed a delicate energetic balance involving the S380 insertion and E381–R197 salt bridge, which collectively tune the activation threshold. Molecular dynamics simulations of ACN mutants further revealed increased flexibility at both HBS and RCL domains, consistent with concerted allosteric coupling. Together, these results provide new mechanistic insights into the structural basis of AT activation and suggest avenues for engineering heparin-independent AT variants. Full article
(This article belongs to the Special Issue Proteases and Their Inhibitors: From Biochemistry to Applications)
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