Around 50 different chemotypes were described so far to possess carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action, through five different inhibition mechanisms: zinc coordination, anchoring to the zinc-coordinated water molecule; occluding the active site entrance; out of the active site binding, and halogen bond formation with the proton shuttling residues. It is conceivable that future research will evidence new CA inhibitors (CAIs) and novel mechanisms of inhibition. Presently, the emerging trends in CAI research include, apart the search for new inhibitors, the design of hybrid drugs incorporating CAIs and other pharmacological agents, the design of PROTACs targeting various CA isoforms, as well as expanding the clinical utility of such compounds for the management of tumors, cerebral ischemia, arthritis, neuropathic pain, and infections produced by bacteria, fungi, and protozoans. From the biotechnological viewpoint, CAs may be highly useful for carbon dioxide capture technologies.

Carbonic anhydrases (CAs) are highly efficient metalloenzymes catalyzing the reversible conversion of carbon dioxide (CO2) into bicarbonate (HCO3-) and protons (H+). Over the past decades, CAs have been employed across diverse industrial and environmental applications, including carbon management and CO2 capture, chemical synthesis, biomineralization, water treatment, and renewable energy generation. This chapter provides a comprehensive overview of CA-based technologies, emphasizing their transition from laboratory research to pilot- and industrial-scale applications. Key topics covered include enzyme-assisted CO2 absorption, reactor and solvent design, enzyme immobilization, and hybrid systems integrating chemical, biological, or electrochemical conversion. The chapter also examines operational challenges, mitigation strategies, and future perspectives, highlighting how CAs can enable sustainable, low-energy, and value-added processes. It illustrates the integration of mechanistic insights, process design, and real-world examples, providing a valuable resource for both researchers and industrial practitioners.

Carbonic anhydrase inhibitors (CAIs) have long been used as diuretics, topically acting antiglaucoma agents, anticonvulsants, and for the treatment of altitude sickness. Lately, they have shown promising results as anti-obesity, antimicrobial, and mainly antitumor agents. Recent studies have reported the efficacy of CAIs in treating inflammatory conditions such as arthritis and neuropathic pain. Moreover, a polypharmacological profile has been demonstrated for sulfonamide COX-2 inhibitors such as celecoxib, which also effectively inhibit CAs. Additionally, emerging research showed the effectiveness of CAIs in cerebral ischemia, where they help protect brain tissue by modulating pH levels and reducing acidosis-induced neuronal damage.

Eleven carbonic anhydrase isoforms are known to be present in different parts of the central nervous system and are involved in signal transduction, cerebral fluid homeostasis, bicarbonate generation, respiratory response to carbon dioxide, seizure activity, and fluid and ion compartmentation. Therefore, carbonic anhydrase inhibitors profoundly influence several neurological therapeutic approaches. Many CAIs, such as acetazolamide, zonisamide, topiramate, lacosamide, and levetiracetam are successfully used in cerebral pathologies. To improve the efficacy, selectivity, and to minimize the side effects, the bespoke medications are engineered using "one-tail approach" and their pharmacological mechanisms of actions are elucidated.

Tumor hypoxia and extracellular acidosis are hallmarks of the tumor microenvironment that promote cancer progression, metabolic adaptation, and resistance to therapy. Among the molecular mediators of these processes, carbonic anhydrase IX (CA IX) and carbonic anhydrase XII (CA XII) play central roles in maintaining intracellular pH homeostasis and facilitating tumor cell survival under hypoxic stress, making them highly attractive targets for selective therapeutic intervention. This has prompted an effort to inhibit specific CA isoforms, as an anticancer therapeutic strategy with small molecule inhibitors, one of which (SLC-0111) completed Phase I clinical trials. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. Recent findings have revealed that CA IX and CA XII are not only critical for pH regulation but also intersect with key metabolic and redox pathways, including ferroptosis, glutathione metabolism, and mitochondrial iron-sulfur cluster biogenesis. Parallel advances in drug design have expanded this therapeutic paradigm through the development of dual-target inhibitors, combining CA IX/XII inhibition with modulation of other cancer-associated pathways. Beyond small-molecule inhibitors, antibody-based approaches have reached clinical and preclinical development as imaging agents, radioimmunotherapeutics, antibody-drug conjugates, and nanomaterial conjugates. Collectively, these strategies highlight the potential of exploiting the metabolic vulnerabilities of hypoxic tumors by co-targeting CA IX/XII with complementary redox or survival pathways, paving the way toward rational polypharmacology in precision oncology.

Ophthalmology is the branch of medicine devoted to the study, diagnosis, and treatment of disorders affecting the eye and visual system, as glaucoma is. It is a leading cause of irreversible blindness worldwide and is commonly diagnosed solely in advanced stages of the disease when important and irreversible losses of visual field have already occurred. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme Carbonic Anhydrases. Indeed, CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by mainly reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. This chapter presents an overview of the current CAIs used for treating glaucoma and introduces the latest pharmaceutical advancements in this field.

Human carbonic anhydrases (hCAs) are emerging as increasingly relevant therapeutic targets due to their involvement in a broad spectrum of pathological conditions, ranging from glaucoma and epilepsy to cancer, neuroinflammation, metabolic disorders, and obesity. The coexistence of 15 isoforms with distinct catalytic activities and tissue distributions makes selectivity a central challenge in the development of CA inhibitors (CAIs). Recent advances in computational chemistry, artificial intelligence (AI), machine learning (ML), and Structure-Based Drug Design (SBDD) have significantly accelerated the identification of new chemotypes and selective modulators.This chapter provides a comprehensive overview of in silico strategies applied to CAIs, including pharmacophore modeling, Virtual Screening, docking, molecular dynamics (MD), MM-GBSA, and AI-driven predictive modeling. Case studies illustrate how Ligand-Based and Structure-Based approaches have led to the discovery of selective inhibitors for hCAs. A special emphasis is placed on structure-function relationships, including peculiar active-site features responsible for isoform differentiation and exploitable for rational ligand design.Furthermore, the chapter highlights recent ML- and DL-based frameworks trained on large biochemical datasets, capable of predicting potency and selectivity with high accuracy. Notably, the integration of explainable AI tools and experimental validation demonstrates the potential of computational pipelines in guiding hit identification and optimization.Overall, this chapter underscores the increasingly synergistic role of computational methodologies and AI in the development of selective CAIs.

Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and play essential roles in numerous physiological and pathological processes. Over the past decades, carbonic anhydrase inhibitors (CAIs) have emerged as valuable therapeutic agents for the treatment of a variety of human disorders, including glaucoma, epilepsy, altitude sickness, and, more recently, cancer and infectious diseases. This chapter provides a comprehensive overview of the principles and strategies underlying the rational design and synthesis of CA inhibitors. The two fundamental medicinal chemistry approaches for CAI development, the "ring approach" and the "tail approach," are discussed in detail, emphasizing the versatility and effectiveness of these strategies in optimizing binding affinity and enhancing isoform selectivity. Both classical zinc-binding inhibitors, such as sulfonamides and related chemotypes, and nonclassical inhibitors acting through alternative mechanisms are discussed. Among nonclassical inhibitors, particular attention is devoted to natural product-derived scaffolds, such as coumarins and polyamines, which have gained considerable interest due to their selective inhibition of the tumor-associated isoforms hCA IX/hCA XII, and hCA IV, respectively. The chapter also evaluates the increasing number of recently reported nonclassical chemotypes for which X-ray crystal structures in adduct with the enzymes are however not available. Finally, an overview of the main synthetic methodologies employed for the preparation of the different classes of CA inhibitors is presented, providing practical insights into the chemical strategies most commonly used in this field.

The catalytic mechanism of carbonic anhydrase (CA, EC 4.2.1.1) at least for the physiological CO2 hydration is well understood, with the CO2-bicarbonate interconversion due to the nucleophilic attack of a zinc hydroxide species on the substrate molecule bound in a hydrophobic pocket, followed by a proton transfer reaction for the generation of the nucleophilic species of the enzyme, which is also the rate-determining one. There are five CA inhibition mechanisms described in detail to date, including (i) zinc-binding: (ii) anchoring to the zinc-bound water/hydroxide ion; (iii) occluding the active-site entrance; (iv) binding outside the active site; and (v) halogen-bond interaction with the proton shuttle of the enzyme. More than 50 different chemotypes were identified, which act in this way, whereas there are few compounds for which the inhibition mechanism is not clear yet. The many new classes of CA inhibitors also allowed the identification of isoform-selective agents for the many CA isoforms described in humans and thus, also the possibility of new pharmacological applications.

Carbonic anhydrases (CAs) form a widely distributed superfamily of metalloenzymes, characterized by considerable structural diversity. These enzymes catalyze the reversible conversion of carbon dioxide into bicarbonate and protons. While they all perform this fundamental reaction, CAs show notable structural plasticity, with eight classes (α, β, γ, δ, ζ, η, θ, and ι) that have evolved independently to optimize CO₂ hydration under a range of cellular, physiological, and ecological conditions. Their catalytic efficiency plays a crucial role in several biological processes, including acid-base balance, respiratory gas exchange, renal bicarbonate reabsorption, metabolic regulation, and photosynthetic carbon fixation. Isoform-specific expression allows CAs to act in multiple cellular contexts. They contribute to signaling pathways, help maintain pH balance, function within tissue-specific environments. When these enzymes are not properly regulated, they can be associated with a variety of health issues, including renal tubular acidosis, osteopetrosis, neurological disorders, and cancer progression. Evolution has shaped enzymes in different species to have similar active sites, flexible metal use, and varied protein assemblies, all helping them adapt to challenges like limited metal ions availability and changing CO₂ levels. CAs are not just important in biology. These metalloenzymes are also key targets for treating cancer, eye conditions, and infections. Besides, they show great promise as enzymes for capturing CO₂ and for other biotechnological applications. This chapter offers a thorough introduction to CAs, exploring their biology, how their structures and functions have evolved, and their potential applications, showing how these enzymes link the worlds of science, medicine, and the environment.

The COVID-19 pandemic has impacted millions of people worldwide, and recent studies have shown that SARS-CoV-2 infection can lead to an Alzheimer's-like neuropathological and biomarker phenotype, as well as clinical symptoms of "brain fog". This raises an intriguing question: "How and where might the molecular pathways underlying SARS-CoV-2 infection and Alzheimer's disease (AD) converge?" One common feature of both SARS-CoV-2 infection and AD is the alteration of the endomembrane system, particularly the fragmentation of the Golgi apparatus. In this review article, we summarize the existing literature on SARS-CoV-2 infection biology and speculate about the potential mechanisms linking Golgi defects, SARS-CoV-2 infection, and neurodegeneration.

The Golgi apparatus is a highly dynamic organelle and central to the regulation of a variety of cell processes. Here we review the relationship between the morphology and function of this organelle, especially to in relation to neuronal development and maintenance. The morphology of the Golgi organelle in neurons is unique as it is present as a Golgi ribbon in the cell body and also as dendritic Golgi elements, known as Golgi outposts, in the neuronal extensions. Many neurodegenerative diseases are associated with the loss of the Golgi ribbon structure and the appearance of dispersed and fragmented Golgi units in the cell body/soma. Here we summarise a key role of the Golgi to limit the proteolytic processing of amyloid precursor protein (APP) by secretases and protect healthy cells, and the perturbations of Golgi morphology arising from increased APP processing and amyloid β production in Alzheimer's disease, the most common of the neurodegenerative disease. The potential consequence of changes in the Golgi architecture and increase of amyloid β production on neuronal function is also considered.

The Golgi apparatus has important, well characterised functions in the trafficking, processing, and post-translational modification of proteins and lipids. However, roles in other cellular processes are increasingly reported, including autophagy, apoptosis, DNA repair, and cytoskeletal (microtubules and actin) function. The Golgi therefore serves as a regulatory hub for multiple signalling pathways that maintain essential cellular activities. The Golgi normally consists of flattened stacks of membrane (cisternae), but during normal physiology and pathological conditions it 'fragments', resulting in altered morphology and distribution. This is well described as an early pathological feature of many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and prion diseases, and amyotrophic lateral sclerosis (ALS). These age-related conditions are characterised by the death of neurons: highly specialised, unique cells that form the foundation of the nervous system. Interestingly, many Golgi-related functions are also dysregulated in these diseases. However, this has received relatively little attention compared to other pathogenic mechanisms. The Golgi apparatus in neurons shares features common to other eukaryotic cells but it also has unique properties, such as the presence of distinctive assemblies: Golgi outposts and satellites, which remain poorly characterised. Here we discuss the increasing evidence describing dysfunction and fragmentation of the Golgi apparatus and its possible role in the pathogenesis of neurodegenerative diseases.

KIT, a receptor protein tyrosine kinase (RTK), is localized in the plasma membrane and binds stem cell factor. A cancer-causing permanently active mutant of KIT (KIT[mut]) accumulates aberrantly in intracellular compartments. Oncogenic RTK mutants other than KIT[mut] also exhibit characteristic organelle localization, unlike their wild-type counterparts. However, the precise subcellular localization of RTK[mut] and its biological significance in oncogenic signaling remain unclear. Recent studies have shown that in gastrointestinal stromal tumors (GISTs), KIT[mut] is inappropriately retained in the Golgi/trans-Golgi network (TGN) area in a manner dependent on its tyrosine kinase activity. It is trapped in the biosynthetic secretory pathway in which normal RTK trafficking occurs. Importantly, KIT[mut] is activated and exerts oncogenic signaling predominantly in the Golgi/TGN of GIST cells. Recently, key players in the Golgi retention of KIT[mut] have been reported, but they are unlikely to be involved in the intracellular retention of other RTKs, suggesting that the retention of individual RTKs is regulated by different molecular mechanisms. Here, we review the present knowledge on KIT retention in the Golgi/TGN region in GISTs, molecular mechanisms underlying this retention, and the aberrant localization of other RTK mutants. We also discuss strategies for the medical development of RTK inhibition by blocking intracellular trafficking.