ABSTRACT Introduction The Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer. Areas covered Recent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past five years related to both the discovery and development of FXR targeting drugs. Expert Opinion FXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators.

ABSTRACT Introduction SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer. Areas covered The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated. Expert opinion SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.

ABSTRACT Introduction Proprotein convertase subtilisin/kexin 9 (PCSK9) plays a crucial role in breaking down the hepatic low-density lipoprotein receptor (LDLR), thereby influencing the levels of circulating low-density lipoprotein cholesterol (LDL-C). Consequently, inhibiting PCSK9 through suitable ligands has been established as a validated therapeutic strategy for combating hypercholesterolemia and cardiovascular diseases. Area covered Patent literature claiming novel compounds inhibiting PCSK9 disclosed from 2018 to June 2023 available in the espacenet database, which contains more than 150 million patent documents from over 100 patent-granting authorities worldwide. Expert opinion The undisputable beneficial influence of PCSK9 as a pharmacological target has prompted numerous private and public institutions to patent chemical frameworks as inhibitors of PCSK9. While several compounds have advanced to clinical trials for treating hypercholesterolemia, they have not completed these trials yet. These compounds must contend in a complex market where new, costly, and advanced drugs, such as monoclonal antibodies and siRNA, are prescribed instead of inexpensive and less potent statins.

ABSTRACT Introduction Bacterial Membrane Vesicles (MVs) play important roles in cell-to-cell communication and transport of several molecules. Such structures are essential components of Extracellular Polymeric Substances (EPS) biofilm matrix of many bacterial species displaying a structural function and a role in virulence and pathogenesis. Areas covered In this review were included original articles from the last ten years by searching the keywords ‘biofilm’ and ‘vesicles’ on PUBMED and Scopus databases. The articles available in literature mainly describe a positive correlation between bacterial MVs and biofilms formation. The research on Espacenet and Google Patent databases underlines the available patents related to the application of both biofilm MVs and planktonic MVs in inhibiting biofilm formation. Expert opinion This review covers and analyzes recent advances in the study of the relationship between bacterial vesicles and biofilm. The huge number of papers discussing the role of MVs confirms the interest aimed at developing new applications in the medical field. The study of the MVs composition and biogenesis may contribute to the identification of components which could be (i) the target for the development of new drugs inhibiting the biofilm establishment; (ii) candidates for the development of vaccines; (iii) biomarkers for the diagnosis of bacterial infections.

ABSTRACT Introduction The oral cavity harbors an extensive array of over 700 microorganisms, forming the most complex biome of the entire human body, with bacterial species being the most abundant. Oral diseases, e.g. periodontitis and caries, are strictly associated with bacterial dysbiosis. Porphyromonas gingivalis and Streptococcus mutans stand out among bacteria colonizing the oral cavity. Areas covered After a brief overview of the bacterial populations in the oral cavity and their roles in regulating (flora) oral cavity or causing diseases like periodontal and cariogenic pathogens, we focused our attention on P. gingivalis and S. mutans, searching for the last-5-year patents dealing with the proposal of new strategies to fight their infections. Following the PRISMA protocol, we filtered the results and analyzed over 100 applied/granted patents, to provide an in-depth insight into this R&D scenario. Expert opinion Several antibacterial proposals have been patented in this period, from both chemical – peptides and small molecules – and biological – probiotics and antibodies – sources, along with natural extracts, polymers, and drug delivery systems. Most of the inventors are from China and Korea and their studies also investigated anti-inflammatory and antioxidant effects, being beneficial to oral health through a prophylactic, protective, or curative effect.

ABSTRACT Introduction Carbonic anhydrases (CAs, EC 4.2.1.1) play a pivotal role in the regulation of carbon dioxide , bicarbonate, and hydrogen ions within bacterial cells, ensuring pH homeostasis and facilitating energy production. We conducted a systematic literature search (PubMed, Web of Science, and Google Scholar) to examine the intricate interplay between CAs and bacterial metabolism, revealing the potential of CA inhibitors (CAIs) as innovative therapeutic agents against pathogenic bacteria. Area covered Inhibition of bacterial CAs was explored in various pathogens, emphasizing the CA roles in microbial virulence, survival, and adaptability. Escherichia coli, a valid and convenient model microorganism, was recently used to investigate the effects of acetazolamide (AAZ) on the bacterial life cycle. Furthermore, the effectiveness of CAIs against pathogenic bacteria has been further substantiated for Vancomycin-Resistant Enterococci (VRE) and antibiotic-resistant Neisseria gonorrhoeae strains. Expert opinion CAIs target bacterial metabolic pathways, offering alternatives to conventional therapies. They hold promise against drug-resistant microorganisms such as VRE and N. gonorrhoeae strains. CAIs offer promising avenues for addressing antibiotic resistance and underscore their potential as novel antibacterial agents. Recognizing the central role of CAs in bacterial growth and pathogenicity will pave the way for innovative infection control and treatment strategies possibly also for other antibiotic resistant species.

ABSTRACT Introduction Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. The BET family consists of four members, each of which contains two bromodomains (BD1 and BD2) able to recognize the acetylated mark. Pan-BET inhibitors (BETi) have shown a promising anticancer potential in many clinical trials; however, their further development has been in part hampered by the side effects due to their lack of selectivity. Mounting evidence suggests that BD1 is primarily involved in cancer and that its selective inhibition can phenocopy the anticancer effects of pan-BETi with increased tolerability. Therefore, the development of BD1 selective inhibitors is highly pursed in both academia and industry. Areas covered This review aims at giving an overview of the patent literature of BD1-selective BETi between 2014 and 2023. WIPO, USPTO, EPO, and SciFinder® databases were used for the search of patents. Expert opinion The development of BD1-selective BETi, despite challenging, is highly desirable as it could have a great impact on the development of new safer anticancer therapeutics. Several strategies could be applied to discover potent and selective compounds with limited side effects.

ABSTRACT Introduction Vibrio cholerae bacteria cause an infection characterized by acute diarrheal illness in the intestine. Cholera is sustained by people swallowing contaminated food or water. Even though symptoms can be mild, if untreated disease becomes severe and life-threatening, especially in low-income countries. Areas covered After a description of the most recent literature on the pathophysiology of this infection, we searched for patents and literature articles following the PRISMA guidelines, filtering the results disclosed from 2020 to present. Moreover, some innovative molecular targets (e.g., carbonic anhydrases) and pathways to counteract this rising problem were also discussed in terms of design, structure-activity relationships and structural analyses. Expert opinion This review aims to cover and analyze the most recent advances on the new druggable targets and bioactive compounds against this fastidious pathogen, overcoming the use of old antibiotics which currently suffer from high resistance rate.

ABSTRACT Introduction Antibacterial photodynamic therapy presents a promising alternative to antibiotics, with potential against multidrug-resistant bacteria, offering broad-spectrum action, reduced resistance risk, and improved tissue selectivity. Areas covered This manuscript reviews patent literature in the field of antibacterial photodynamic therapy through the period of 2019–2023. All data are from the US and European patent databases and SciFinder. Expert Opinion Antibacterial photodynamic therapy (PDT) is an appealing approach for treating bacterial infections, especially biofilm-related ones, by releasing reactive oxygen species (ROS) upon light activation. Its success is driven by a growing variety of photosensitizers (PSs) with tailored properties, like water solubility, controllable surface charge, and ROS generation efficiency. Among them, Aggregation Induced Emission (AIE)-type PSs are promising, demonstrating enhanced efficacy when aggregated in biological environments. However, the penetration of pristine PSs into bacterial biofilms within deep tissues or complex anatomical regions is limited, reducing their antibacterial effectiveness. To address this, nanotechnology has been integrated into antibacterial PDT to synthesize various nano-PSs. This adaptability allows seamless integration with other antimicrobial treatments, offering a comprehensive approach to combat localized infections, especially in dentistry and dermatology. By combining PSs with complementary therapies, antibacterial PDT offers a multifaceted strategy for effective microbial control and management.

ABSTRACT Introduction The TGF-β signaling pathway is a complex network that plays a crucial role in regulating essential biological functions and is implicated in the onset and progression of multiple diseases. This review highlights the recent advancements in developing inhibitors targeting the TGF-β signaling pathway and their potential therapeutic applications in various diseases. Area covered The review discusses patents on active molecules related to the TGF-β signaling pathway, focusing on three strategies: TGF-β activity inhibition, blocking TGF-β receptor binding, and disruption of the signaling pathway using small molecule inhibitors. Combination therapies and the development of fusion proteins targeting multiple pathways are also explored. The literature search was conducted using the Cortellis Drug Discovery Intelligence database, covering patents from 2021 onwards. Expert opinion The development of drugs targeting the TGF-β signaling pathway has made significant progress in recent years. However, addressing challenges such as specificity, systemic toxicity, and patient selection is crucial for their successful clinical application. Targeting the TGF-β signaling pathway holds promise as a promising approach for the treatment of various diseases.