Enzymes Pub Date : 2026-01-01 Epub Date: 2026-08-12 DOI: 10.1016/bs.enz.2026.03.004

Antoine Dufour, Claudiu T Supuran

{"title":"Overview of matrix metalloproteinases (MMPs) in health and disease.","authors":"Antoine Dufour, Claudiu T Supuran","doi":"10.1016/bs.enz.2026.03.004","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.03.004","url":null,"abstract":"Matrix metalloproteinases (MMPs) are a family of structurally related, zinc-dependent endopeptidases with broad substrate specificity, extending far beyond fibrillar collagens to include chemokines, cytokines, growth factors, cell-surface receptors and diverse extracellular matrix (ECM) components. In addition to their well-established proteolytic functions, MMPs can exert non-proteolytic effects through scaffolding roles, interactions with other membrane proteins, or modulation of cell-cell and cell-matrix contacts. Through these catalytic and non-catalytic mechanisms, MMPs influence cell signaling, immunity, barrier function, ECM remodeling, and tissue homeostasis, positioning them as central regulators in both normal physiology and a wide spectrum of acute and chronic diseases. Their dual capacity to either promote tissue repair and resolution or drive inflammation, fibrosis and degeneration, together with the mixed history of broad-spectrum and selective MMP inhibitors in the clinic, has reframed MMPs from simple \"matrix-degrading enzymes\" to context-dependent, temporally regulated modulators that remain compelling yet challenging therapeutic targets. Importantly, many MMP family members remain poorly characterized in specific tissue, cellular or disease contexts, and for several MMPs, only a limited set of physiological substrates is known or confidently validated in vivo. This book will present contemporary aspects of MMP biology, their context-dependent roles in health and disease, current generations of MMP inhibitors, and both the conceptual and practical challenges, as well as emerging opportunities, in the rational design and development of MMP-targeted therapeutics.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"60 ","pages":"1-35"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Challenges and opportunities for developing selective carbonic anhydrase inhibitors and activators for vertebrate isoforms. 开发脊椎动物亚型选择性碳酸酐酶抑制剂和活化剂的挑战和机遇。

Enzymes Pub Date : 2026-01-01 Epub Date: 2026-03-30 DOI: 10.1016/bs.enz.2026.03.003

Claudiu T Supuran

{"title":"Challenges and opportunities for developing selective carbonic anhydrase inhibitors and activators for vertebrate isoforms.","authors":"Claudiu T Supuran","doi":"10.1016/bs.enz.2026.03.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.03.003","url":null,"abstract":"Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors of the sulfonamide/sulfamate type, such as acetazolamide, thiazides/high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, antiepileptics (sulthiame, topiramate, zonisamide), or non-steroidal anti-inflammatory agents such as celecoxib and polmacoxib, are effective inhibitors of most CA isoforms present in vertebrates but their clinical use in various pathologies is associated with side effects. Significant efforts were done in the last decades for developing isoform-selective inhibitors for all 12 catalytically active mammalian isoforms, with important results being obtained by using the tail approach or by the discovery of new inhibitory chemotypes, such as the coumarins and their derivatives, the boron/selenium-containing compounds, etc. SLC-0111, an antitumor sulfonamide in clinical development is an example of a successful strategy emerged by using the tail approach, this compound being a selective inhibitor of the tumor-associated isoforms CA IX and XII. Coumarins, sulfocoumarins and some boron-containing compounds show significant levels of isoform-selective inhibition against many CA isoforms too. Few compounds, on the other hand, show selectivity for inhibiting microbial over vertebrate isoforms, which is a considerable challenge for developing anti-infectives based on CA inhibitors. At the moment, only coumarins act as class-selective inhibitors for α- and η-CAs, not inhibiting significantly other CA classes (β-, γ-, δ-, ζ-, θ- and ι-CAs). Selective CA activators for the mammalian isoforms are not available yet, although they might lead to relevant pharmacological applications for the management of neurodegenerations, emotional memory disorders, obsessive-compulsive disorders, phobias, post-traumatic stress. Finding more effective isoform-selective and more importantly, class-selective modulators of activity for vertebrate CAs might afford opportunities for innovative therapeutic/pharmacological applications.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"59 ","pages":"299-342"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Challenges for developing selective fungal/protozoal carbonic anhydrase inhibitors as anti-infectives. 开发选择性真菌/原生动物碳酸酐酶抑制剂作为抗感染的挑战。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-07-30 DOI: 10.1016/bs.enz.2025.05.005

Claudiu T Supuran

{"title":"Challenges for developing selective fungal/protozoal carbonic anhydrase inhibitors as anti-infectives.","authors":"Claudiu T Supuran","doi":"10.1016/bs.enz.2025.05.005","DOIUrl":"10.1016/bs.enz.2025.05.005","url":null,"abstract":"Carbonic anhydrases (CAs, EC 4.2.1.1) were characterized in several fungi (Cryptococcus neoformans, Candida albicans and C. glabrata, Saccharomyces cerevisiae, Malassezia globosa, M. restricta and M. pachydermatis, Sordaria macrospora, Aspergillus fumigatus and A. oryzae) and protozoans (Trypanosoma cruzi, Leishmania donovani chagasi, Plasmodium falciparum, Entamoeba histolytica, Trichomonas vaginalis, Toxoplasma gondii) being also shown that they are present in Acanthamoeba castellanii. These enzymes belong to various genetic families (α- and β-CAs for fungi, α-, β-, γ- and η-classes for protozoans), showed significant CO2 hydrase activity and a vast number of inhibitors were detected belonging to the inorganic anions, sulfonamides, phenols, mono-/dithiocarbamates, boronic acids, benzoxaboroles, or coumarins. However, few of them showed anti-infective properties in vivo or ex vivo, due to the limited number of such studies. Promising results were however obtained with sulfonamides showing antimalarial, anti-Malassezia spp., anti-T. cruzi and anti-leishmanial action against various strains of these pathogens, sometimes resistant to clinically used drugs. The main challenges for obtaining effective antifungals/antiprotozoan agents based on CA inhibitors are: (i) the complex life cycles of most of these pathogens, which frequently have different stages, hosts and diverse gene expression and metabolic patterns; (ii) lack of detailed structural data for many such enzymes; (iii) lack of focused drug design campaigns for the specific enzymes found in these pathogens, and (iv) lack of simple, inexpensive in vivo models for their testing. Future work in the field that should address these limitations might lead to relevant developments for obtaining novel anti-infectives.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"229-250"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Entamoeba histolytica carbonic anhydrase. 溶组织内阿米巴碳酸酐酶。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-08-19 DOI: 10.1016/bs.enz.2025.07.006

Seppo Parkkila

{"title":"Entamoeba histolytica carbonic anhydrase.","authors":"Seppo Parkkila","doi":"10.1016/bs.enz.2025.07.006","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.07.006","url":null,"abstract":"Amoebiasis, caused by Entamoeba histolytica, remains a major public health issue, particularly in developing countries with poor sanitation. It is also a significant challenge among those who travel to endemic areas, causing, in many cases, so-called traveler diarrhea. Approximately 10 percent of the global population is estimated to be affected by this parasitic infection. The primary route of transmission is the consumption of food or water contaminated with E. histolytica cysts. While most infected individuals may remain asymptomatic, some develop severe complications, including hemorrhagic colitis, liver abscesses, and, in extreme cases, colonic perforation. It has been estimated that amoebiasis is responsible for nearly 100,000 deaths annually. Standard treatment for amoebic colitis involves a combination of luminal agents (such as paromomycin, diloxanide furoate, and diiodohydroxyquin) and tissue amoebicides (including metronidazole and tinidazole). Although these treatments are effective, new therapeutic options to improve patient outcomes are needed. One promising avenue for drug discovery is the β-carbonic anhydrase enzyme (EhiCA) of E. histolytica, which has emerged as a potential target for novel antiamoebic therapies. EhiCA was recently produced as a recombinant protein and has been used in kinetic and inhibition studies with various sulfonamides and anions, with promising results.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"219-228"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Viral proteases: Structural basis of function, evolution, and drug design. 病毒蛋白酶：功能、进化和药物设计的结构基础。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-08-12 DOI: 10.1016/bs.enz.2025.06.004

Luigi Franklin Di Costanzo

引用次数: 0

Trichomonas vaginalis carbonic anhydrase. 阴道毛滴虫碳酸酐酶。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-07-16 DOI: 10.1016/bs.enz.2025.07.002

Seppo Parkkila

引用次数: 0

Saccharomyces cerevesiae, Candida spp. and Cryptococcus neoformans β-CAs. 酿酒酵母菌，假丝酵母菌和新型隐球菌β-CAs。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-07-19 DOI: 10.1016/bs.enz.2025.07.001

Anna Di Fiore, Martina Buonanno, Davide Esposito, Katia D'Ambrosio, Emma Langella, Giuseppina De Simone, Vincenzo Alterio, Simona Maria Monti

引用次数: 0

Plasmodium falciparum η-carbonic anhydrase. 恶性疟原虫η-碳酸酐酶。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-06-27 DOI: 10.1016/bs.enz.2025.05.002

Claudiu T Supuran, Clemente Capasso

{"title":"Plasmodium falciparum η-carbonic anhydrase.","authors":"Claudiu T Supuran, Clemente Capasso","doi":"10.1016/bs.enz.2025.05.002","DOIUrl":"10.1016/bs.enz.2025.05.002","url":null,"abstract":"Malaria parasites belonging to the genus Plasmodium encode for a carbonic anhydrase (CA, EC 4.2.1.1) originally considered to belong to the α-class, which has been investigated starting with 2004 as a potential antimalarial target, considering the observation that CA levels in red blood cells infected with these parasites are much higher compared to those of uninfected cells. In plasmodia, CA is involved in metabolic pathways leading to the biosynthesis of pyrimidines, which are scarcely present in the blood of infected hosts, making this enzyme crucial for the life cycle of the parasite in many intraerythrocytic stages of its development. It has been then shown in 2014 that P. falciparum CA (PfCA) belongs in fact to a new CA genetic class, the η-CA, characterized by a particular zinc ion coordination within the active site, with two histidine and a glutamine as protein ligands. A short, truncated and longer PfCA forms have been cloned and characterized in detail, being shown that they act as efficient catalysts for the hydration of CO2 to bicarbonate and protons, but neither of them were crystallized for the moment, and their 3D structure is not known. PfCA inhibition with anions, sulfonamides, phenols and coumarins has been investigated too, with many low nanomolar in vitro inhibitors being detected. Only for acetazolamide and an ureido-substituted benzenesulfonamide it has been demonstrated a potent growth inhibition of the pathogen in P. falciparum infected red blood cells. Although these results are encouraging but rather preliminary, η-CAs from malaria-producing protozoans and presumably other organisms encoding them, may be considered as innovative drug targets for obtaining anti-infectives with new mechanisms of action but these enzymes should be investigated in more details in order to better understand their structure and physiological/pathological roles.","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"113-127"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational approaches for designing viral protease inhibitors. 设计病毒蛋白酶抑制剂的计算方法。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-07-23 DOI: 10.1016/bs.enz.2025.06.005

Alessandro Bonardi

引用次数: 0

Toxoplasma gondii, babesia, and other protozoan carbonic anhydrases. 刚地弓形虫，巴贝虫和其他原生动物的碳酸酐酶。

Enzymes Pub Date : 2025-01-01 Epub Date: 2025-07-08 DOI: 10.1016/bs.enz.2025.05.004

Clemente Capasso, Claudiu T Supuran

引用次数: 0

Enzymes最新文献