EnzymesPub Date : 2025-01-01Epub Date: 2025-06-27DOI: 10.1016/bs.enz.2025.05.001
Claudiu T Supuran, Clemente Capasso
{"title":"Overview on fungal and protozoan carbonic anhydrases.","authors":"Claudiu T Supuran, Clemente Capasso","doi":"10.1016/bs.enz.2025.05.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.001","url":null,"abstract":"<p><p>An overview of carbonic anhydrases (CAs) in fungi and protozoa is provided, emphasizing their evolutionary significance, functional diversity, and implications for human health. CAs are metalloenzymes that catalyze the reversible hydration of carbon dioxide, playing crucial roles in cellular homeostasis, pH regulation, and metabolic adaptation. In fungi, α- and β-class CAs are predominant, facilitating growth and virulence, particularly in pathogenic species such as Candida spp., Cryptococcus neoformans and many others. Protozoa exhibit a broader range of CA classes, including the recently identified η-class in Plasmodium falciparum, which is vital for the survival of the parasite and presents a significant potential as a drug target. The evolutionary trajectories of CAs reflect adaptations to diverse ecological niches, with gene duplication leading to functional diversification. Understanding the biochemical properties and regulatory mechanisms of CAs in these organisms can lead to innovative therapeutic strategies against fungal and protozoan infections, highlighting their potential as drug and diagnostic targets.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252054","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}
EnzymesPub Date : 2025-01-01Epub Date: 2025-07-23DOI: 10.1016/bs.enz.2025.06.001
Stefano Rusconi, Niccolò Paoletti, Claudiu T Supuran
{"title":"HIV protease and its inhibition.","authors":"Stefano Rusconi, Niccolò Paoletti, Claudiu T Supuran","doi":"10.1016/bs.enz.2025.06.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.06.001","url":null,"abstract":"<p><p>The HIV protease (HPR) is a virus-specific aspartic protease responsible for processing the polyproteins of gag and gag-pol during virion maturation and for the proliferation of HIV. The activity of HPR is essential for virus infectivity, thus it is an important target for the development of anti-HIV drugs. HPR is only one major viral protease, since there are other proteases, which are specific to HCV or SARS-CoV-2 and are therapeutic targets as well. HPR inhibitors in combination with other classes of anti-HIV drugs are one of the main components of an effective anti-HIV therapy. Nevertheless, upon several circumstances, HIV can develop a discrete pattern of resistance towards one or several HPR inhibitors through the phenomenon of cross-resistance. The aim of our work is to illustrate various features of HPR: its structure, the various mechanisms which lead to its inhibition, the HPR inhibitors which are used in the clinical arena, and the pathways involved in drug resistance, plus the mechanisms to overcome it.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"58 ","pages":"129-149"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524656","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}
EnzymesPub Date : 2025-01-01Epub Date: 2025-07-23DOI: 10.1016/bs.enz.2025.06.007
Andrea Trabocchi
{"title":"The peptidomimetic approach for the design of viral protease inhibitors.","authors":"Andrea Trabocchi","doi":"10.1016/bs.enz.2025.06.007","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.06.007","url":null,"abstract":"<p><p>The transformation of peptides into drug leads is an established approach in medicinal chemistry and drug discovery. Peptidomimetics are designed to mimic the bioactivity of peptides while addressing their limitations, such as poor metabolic stability and low bioavailability, thus resulting in improved receptor affinity and selectivity. Over last decades, a range of synthetic strategies has emerged to improve the pharmacological properties of these molecules through local and global conformational restrictions and introducing secondary structure mimetics. Herein the essential tools and methodologies in peptidomimetic design are reported with highlights to their therapeutic relevance, particularly in antiviral drug development. Peptidomimetics have shown notable success in targeting viral proteases as key enzymes involved in the life cycle of several pathogenic viruses. Case studies involving peptidomimetic inhibitors of HIV protease, HCV NS3/4A protease, SARS-CoV-2 main protease (3CLpro), and the NS2B-NS3 proteases of Zika and Dengue viruses are reported highlighting the efficacy of this approach, emphasizing the potential of peptidomimetic drugs as powerful tools in the treatment of infectious diseases.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"58 ","pages":"93-128"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524701","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}
EnzymesPub Date : 2025-01-01Epub Date: 2025-07-16DOI: 10.1016/bs.enz.2025.05.003
Alane Beatriz Vermelho, Felipe Raposo P Mansoldo, Veronica Silva Cardoso, Kamila Marques Sette, Claudiu T Supuran, Igor Almeida Rodrigues
{"title":"Trypanosoma cruzi and Leishmania spp. CAs.","authors":"Alane Beatriz Vermelho, Felipe Raposo P Mansoldo, Veronica Silva Cardoso, Kamila Marques Sette, Claudiu T Supuran, Igor Almeida Rodrigues","doi":"10.1016/bs.enz.2025.05.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.003","url":null,"abstract":"<p><p>Neglected tropical diseases (NTDs) such as Chagas disease and leishmaniasis represent significant public health challenges due to limited therapeutic options and the emergence of drug-resistant parasites. This chapter explores the potential of carbonic anhydrases (CAs) as novel drug targets in Trypanosoma cruzi and Leishmania spp., two etiologic agents of these diseases. The α-class CA in T. cruzi (TcCA) and the β-class CA in Leishmania donovani chagasi (LdcCA) have been functionally characterized and play essential roles in parasite metabolism, pH regulation, and survival. Several inhibitors, such as sulfonamides, thiols, hydroxamates, and benzoxaboroles, demonstrate potent enzymatic inhibition with promising selectivity over human isoforms. Advances in drug formulation, including nanoemulsions, have enhanced the bioavailability and efficacy of certain compounds. The chapter also discusses structure-activity relationships (SAR), challenges in translating in vitro potency to in vivo efficacy, and the strategic advantages of targeting parasite-specific CAs in combination therapies. These findings support CAs as viable and selective targets for innovative anti-parasitic drug development.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"129-182"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252932","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}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-25DOI: 10.1016/bs.enz.2024.06.001
Francesco Melfi, Simone Carradori, Arianna Granese, Amar Osmanović, Cristina Campestre
{"title":"Drug design of tyrosinase inhibitors.","authors":"Francesco Melfi, Simone Carradori, Arianna Granese, Amar Osmanović, Cristina Campestre","doi":"10.1016/bs.enz.2024.06.001","DOIUrl":"10.1016/bs.enz.2024.06.001","url":null,"abstract":"<p><p>This copper-containing enzyme catalyzes the rate-limiting step for the melanin skin pigment bioproduction. Tyrosinase inhibitors can be exploited as skin whitening agents and food preservatives, opening new scenarios in food, cosmetics, agriculture and medicine. Despite the availability of natural inhibitors (hydroquinone, α-arbutin, kojic acid, retinoids, azelaic acid, resveratrol, caftaric acid, valonea tannin, chrysosplenetin and phenylethyl resorcinol), several synthetic compounds were proposed to overcome side effects and to improve the efficacy of natural agents. This chapter will gather the recent advances about synthetic tyrosinase inhibitors from the MedChem perspective, providing new suggestions for the scaffold-based design of innovative compounds.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"56 ","pages":"111-134"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297670","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}
EnzymesPub Date : 2024-01-01Epub Date: 2024-07-03DOI: 10.1016/bs.enz.2024.05.006
Claudiu T Supuran
{"title":"Challenges for developing bacterial CA inhibitors as novel antibiotics.","authors":"Claudiu T Supuran","doi":"10.1016/bs.enz.2024.05.006","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.006","url":null,"abstract":"<p><p>Acetazolamide, methazolamide, ethoxzolamide and dorzolamide, classical sulfonamide carbonic anhydrase (CA) inhibitors (CAIs) designed for targeting human enzymes, were also shown to effectively inhibit bacterial CAs and were proposed for repurposing as antibacterial agents against several infective agents. CAs belonging to the α-, β- and/or γ-classes from pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, vacomycin resistant enterococci (VRE), Vibrio cholerae, Mycobacterium tuberculosis, Pseudomonas aeruginosa and other bacteria were considered as drug targets for which several classes of potent inhibitors have been developed. Treatment of some of these pathogens with various classes of such CAIs led to an impairment of the bacterial growth, reduced virulence and for drug resistant bacteria, a resensitization to clinically used antibiotics. Here I will discuss the strategies and challenges for obtaining CAIs with enhanced selectivity for inhibiting bacterial versus human enzymes, which may constitute an important weapon for addressing the drug resistance to β-lactams and other clinically used antibiotics.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"383-411"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120829","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}
EnzymesPub Date : 2024-01-01Epub Date: 2024-07-20DOI: 10.1016/bs.enz.2024.06.007
Fabrizio Carta
{"title":"Non-sulfonamide bacterial CA inhibitors.","authors":"Fabrizio Carta","doi":"10.1016/bs.enz.2024.06.007","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.06.007","url":null,"abstract":"<p><p>Non-sulfonamide chemical moieties able to inhibit the bacterial (b) expressed Carbonic Anhydrases (CAs; EC 4.2.1.1) constitute an important alternative to the prototypic modulators discussed in Chapter 6, as give access to large and variegate chemical classes, also of the natural origin. This contribution reports the main classes of compounds profiled in vitro on the bCAs and thus may be worth developing for the validation process of this class of enzymes.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"193-212"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120834","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}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-06DOI: 10.1016/bs.enz.2024.05.007
Reygan E Braga, Fares Z Najar, Chelsea L Murphy, Marianna A Patrauchan
{"title":"Carbonic anhydrases in bacterial pathogens.","authors":"Reygan E Braga, Fares Z Najar, Chelsea L Murphy, Marianna A Patrauchan","doi":"10.1016/bs.enz.2024.05.007","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.007","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) catalyze the reversable hydration of carbon dioxide to bicarbonate placing them into the core of the biochemical carbon cycle. Due to the fundamental importance of their function, they evolved independently into eight classes, three of which have been recently discovered. Most research on CAs has focused on their representatives in eukaryotic organisms, while prokaryotic CAs received significantly less attention. Nevertheless, prokaryotic CAs play a key role in the fundamental ability of the biosphere to acquire CO<sub>2</sub> for photosynthesis and to decompose the organic matter back to CO<sub>2</sub>. They also contribute to a broad spectrum of processes in pathogenic bacteria, enhancing their ability to survive in a host and, therefore, present a promising target for developing antimicrobials. This review focuses on the distribution of CAs among bacterial pathogens and their importance in bacterial virulence and host-pathogen interactions.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"313-342"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120828","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}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-25DOI: 10.1016/bs.enz.2024.06.002
Aslınur Doğan, Suleyman Akocak
{"title":"Natural products as tyrosinase inhibitors.","authors":"Aslınur Doğan, Suleyman Akocak","doi":"10.1016/bs.enz.2024.06.002","DOIUrl":"10.1016/bs.enz.2024.06.002","url":null,"abstract":"<p><p>Tyrosinase is a crucial copper-containing enzyme involved in the production of melanin. Melasma, age spots, and freckles are examples of hyperpigmentation diseases caused by excess production of melanin. Inhibiting tyrosinase activity is a crucial method for treating these disorders along with various applications such as cosmetics, food technology, and medicine. Natural products have proven a rich source of tyrosinase inhibitors, with several molecules from plant, marine, and microbial sources showing potential inhibitory action. This chapter provides a complete overview of natural compounds that have been found as tyrosinase inhibitors, with emphasis on their structures, modes of action, and prospective applications.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"56 ","pages":"85-109"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297671","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}
EnzymesPub Date : 2024-01-01Epub Date: 2024-08-06DOI: 10.1016/bs.enz.2024.05.012
Jenny Parkkinen, Ratul Bhowmik, Martti Tolvanen, Fabrizio Carta, Claudiu T Supuran, Seppo Parkkila, Ashok Aspatwar
{"title":"Mycobacterial β-carbonic anhydrases: Molecular biology, role in the pathogenesis of tuberculosis and inhibition studies.","authors":"Jenny Parkkinen, Ratul Bhowmik, Martti Tolvanen, Fabrizio Carta, Claudiu T Supuran, Seppo Parkkila, Ashok Aspatwar","doi":"10.1016/bs.enz.2024.05.012","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.012","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is still a major global health problem. According to the World Health Organization (WHO), TB still causes more deaths worldwide than any other infectious agent. Drug-sensitive TB is treatable using first-line drugs; treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB requires second- and third-line drugs. However, due to the long duration of treatment, the noncompliance of patients with different levels of resistance of Mtb to these drugs has worsened the situation. Previously developed anti-TB drugs targeted the replication machinery, protein synthesis, and cell wall biosynthesis pathways of Mtb. Therefore, novel drugs targeting alternate pathways crucial for the survival and pathogenesis of Mtb in the human host are needed. The genome of Mtb encodes three β-carbonic anhydrases (CAs) that are fundamental for pH homeostasis, hypoxia, survival, and pathogenesis. Recently, several studies have shown that the β-CAs of Mtb could be inhibited both in vitro and in vivo using small chemical molecules, suggesting that these enzymes could be novel targets for developing anti-TB compounds that are devoid of resistance by Mtb. In addition, homologs of β-CAs are absent in humans; therefore, drugs developed to target these enzymes might have minimal off-target effects. In this work, we describe the roles of β-CAs in Mtb and discuss bioinformatics and cheminformatics tools used in development and discovery of novel inhibitors of these enzymes. In addition, we summarize the in vitro and in vivo studies demonstrating that the β-CAs of Mtb are indeed druggable targets.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"343-381"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120832","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}
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