The Front Cover illustrates pulmonary fungal infection caused by Cryptococcus species. Pathogenic fungi are eukaryotes and structurally similar to human cells, thus making it challenging to develop target-specific antifungal agents. The emergence of drug-resistant fungi has also created a need for novel classes of antifungal therapeutics. Tetrazole-backbone-containing compounds may be novel antifungal drugs with distinct mechanisms against cryptococcosis. Cover design by Nana Nakada and Taiga Miyazaki with special technical support from Rie Matsuura. More information can be found in the Research Article by Nana Nakada, Taiga Miyazaki et al..

In this review, we shed light on how the shapes of the glyco-nanostructures govern cell-specific homing and immune responses. We examine recent advances in glyco-nanostructures of various shapes that modulate carbohydrate–protein interactions. We specifically emphasize glyco-nanostructures constructed from small-molecule amphiphilic carbohydrates, block copolymers, metal-based nanoparticles, and carbon-based materials, highlighting their potential applications in glycobiology.

Abstract

Carbohydrate–protein interactions (CPIs) play a crucial role in the regulation of various physiological and pathological processes within living systems. However, these interactions are typically weak, prompting the development of multivalent probes, including nanoparticles and polymer scaffolds, to enhance the avidity of CPIs. Additionally, the morphologies of glyco-nanostructures can significantly impact protein binding, bacterial adhesion, cellular internalization, and immune responses. In this review, we have examined the advancements in glyco-nanostructures of different shapes that modulate CPIs. We specifically emphasize glyco-nanostructures constructed from small-molecule amphiphilic carbohydrates, block copolymers, metal-based nanoparticles, and carbon-based materials, highlighting their potential applications in glycobiology.

High-contrast and fast-removable fluorinated agents C₁₀F₁₈H₄O₂ and C₁₁F₁₈H₆ for the ¹⁹F MRI method were designed. The synthesis of these compounds is not complicated. The emulsions with these substances were developed, and in vivo MRI studies in laboratory rats were carried out. The substances are non-toxic, and they are excreted from the living organism in ~30 days.

Abstract

¹⁹F MRI is a unique technique for tracking and quantifying the indicator (¹⁹F-MRI label) in vivo without the use of ionizing radiation. Here we report new ¹⁹F-MRI labels, which are compounds with perfluoro-tert-butyl groups: 1,2-bis(perfluoro-tert-butoxy)ethane (C₁₀F₁₈H₄O₂) and 1,3-bis(perfluoro-tert-butyl)propane (C₁₁F₁₈H₆). Both substances contain 18 equivalent ¹⁹F atoms, constituting 68.67 % and 71.25 % of the molecule, respectively. The emulsions with ¹⁹F molecules were prepared and used in ¹⁹F MRI studies in laboratory rats in vivo. The substances demonstrated high contrast properties, good biological inertness and the ability to be rapidly eliminated from the body. We showed that at a dose of 0.34 mg/g of body weight in rats, the time for complete elimination of C₁₀F₁₈H₄O₂ and C₁₁F₁₈H₆ is ∼30 days. The results turned out to be promising for the use of the presented compounds in ¹⁹F MRI applications, especially since they are quite easy to synthesize.

We explored our in-house collection of sulfonamides to identify new potent hCA IX/XII inhibitors. Docking simulations highlighted the docking poses in catalytic sites of hCA IX and hCA XII cavities. These structural findings may help lead to the successful identification of new sulfonamides as adjuvant agents in cancer management.

Abstract

The tumor-expressed human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII have been extensively studied to develop anticancer agents targeting solid tumors in combined therapy. These CA  isoforms are considered key factors in controlling tumor microenvironment (TME) of cancer lines that develop high metastatic activity. Herein, we report the discovery of potent hCA IX/hCA XII inhibitors that were disclosed through a screening campaign on an in-house collection of arylsulfonamides preliminary tested toward other hCAs. Among them, the N-(4-sulfamoylphenyl)naphthalene-2-carboxamide (12) and N-(4-sulfamoylphenyl)-3,4-dihydroisoquinoline-2(1H)-carbothioamide (15) proved to be the most intriguing hCA IX/hCA XII inhibitors displaying favourable selectivity ratios over widespread hCA I and hCA II isoforms. To explore their binding mode, we conducted docking studies that described the poses of the best inhibitors in the catalytic site of hCA IX and hCA XII, thus suggesting the privileged pattern of interactions. These structural findings might further improve the knowledge for a successful identification of new sulfonamides as adjuvant agents in cancer management.

A new series of [1,2,4]triazolo[1,5-c]pyrimidines was investigated at position 2 to obtain potent and selective A₃ #adenosine receptor antagonists. #Docking studies were performed to rationalize these results, particularly with respect to selectivity. The best compound in the series was then tested on #cancer cell lines expressing the target receptor and showed an interesting proliferative effect.

Abstract

The A₃ adenosine receptor is an interesting target whose role in cancer is controversial. In this work, a structural investigation at the 2-position of the [1,2,4]triazolo[1,5-c]pyrimidine nucleus was performed, finding new potent and selective A₃ adenosine receptor antagonists such as the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (20, DZ123) that showed a K_i value of 0.47 nM and an exceptional selectivity profile over the other adenosine receptor subtypes. Computational studies were performed to rationalize the affinity and the selectivity profile of the tested compounds at the A₃ adenosine receptor and the A₁ and A_2A adenosine receptors. Compound 20 was tested on both A₃ adenosine receptor positive cell lines (CHO-A₃AR transfected, THP1 and HCT16) and on A₃ negative cancer cell lines, showing no effect in the latter and a pro-proliferative effect at a low concentration in the former. These interesting results pave the way to further investigation on both the mechanism involved and potential therapeutic applications.

The development of new artesunate hybrid compounds containing benzenesulfonamide chemotypes as antimalarial agents through a dual mechanism of action: fast-acting ROS generation and long-lasting Plasmodium falciparum carbonic anhydrase (PfCA) inhibition.

Abstract

Malaria continues to be a major public health challenge worldwide and, as part of the global effort toward malaria eradication, plasmodium carbonic anhydrases (CAs) have recently been proposed as potential targets for malaria treatment. In this study, a series of eight hybrid compounds combining the Artesunate core with a sulfonamide moiety were synthesized and evaluated for their inhibition potency against the widely expressed human (h) CAs I, II and the isoform from P. falciparum (PfCA). All derivatives demonstrated high inhibition potency against PfCA, achieving a K_I value in the sub-nanomolar range (0.35 nM). Two Compounds showed a selectivity index of 4.1 and 3.1, respectively, against this protozoan isoform compared to hCA II. Three Derivatives showed no cytotoxic effects on human gingival fibroblasts at 50 μM with a high killing rate against both P. falciparum and P. knowlesi strains with IC₅₀ in the sub-nanomolar range, providing a wide therapeutic window. Our findings suggest that these compounds may serve as promising leads for developing new antimalarial drugs and warrant further investigation, including activity against antimalarial-resistant strains, mode of action studies, and in vivo efficacy assessment in preclinical mouse models of malaria.

PEGylation was usually recognized as a gold standard to improve the stability and half-life of protein drugs. Although hugely succussed, the drawbacks of PEGylated proteins, such as accumulated toxicity and anti-PEG antibodies, compromise the full therapeutic potential of protein drugs. With super-hydrophilicity and superior anti-fouling properties, zwitterionic polymer is gradually accepted as an alternative to PEG for protein conjugation. In this review, we discuss a series of features exhibited by protein-zwitterionic polymer conjugate that outperform PEGylated protein.

Abstract

To render protein drugs more suitable for clinical treatment, PEGylation has been widely used to ameliorate their inherent deficiencies, such as poor stability, rapid elimination in the bloodstream, and high immunogenicity. While increasingly PEGylated protein drugs have been approved by the FDA, the non-degradability of PEG and the emergence of anti-PEG antibodies after injection raise concerns about their cumulative chronic toxicity and long-term therapeutic efficacy. Zwitterionic polymer, with a unique structure containing equal amounts of positively charged and negatively charged groups, shows a different hydration behavior to PEG, which may be a superior PEG alternative for protein conjugation. In this concept review, a series of features beyond that of PEGylated protein exhibited by protein-zwitterionic polymer conjugate are discussed and some suggestions are presented for their future direction.

Monoderivatives of fullerenes functionalized with hydrophilic groups make them water soluble, while preserving the hydrophobic fullerene cage. These molecules have intriguing biomedical applications, including drug delivery, photodynamic therapy (PDT), antiviral and antimicrobial activity and reactive oxygen species (ROS)-scavenging abilities. Herein we discuss the synthesis and biomedical applications of water-soluble fullerene monoderivatives and their biological behavior based on their structures. (Image created with BioRender.com.)

Abstract

Monoderivatives of fullerenes functionalized with hydrophilic groups make them water soluble, while preserving the hydrophobic fullerene cage. This class of molecules have intriguing biomedical applications, including drug delivery, photodynamic therapy (PDT), antiviral and antimicrobial activity and reactive oxygen species (ROS)-scavenging abilities. In this Concept we discuss the synthesis and biomedical applications of water-soluble fullerene monoderivatives and their biological behavior based on their structures.

“Click chemistry” and targeted protein degradation – two flourishing trends in medicinal chemistry. May they be a winning combination? In this review, we provide the reader with selected examples offered by the combination of these two approaches trying to find a response to this question.

Abstract

Click chemistry is universally recognized as a powerful strategy for the fast and precise assembly of diverse building blocks. Targeted Protein Degradation (TPD) is a new therapeutic modality based on heterobifunctional small-molecule degraders that provides new opportunities to medicinal chemists dealing with undruggable targets and incurable diseases. Here, we highlight how very recently the TPD field and that of click chemistry have merged, opening up the possibility for fine-tuning the properties of a degrader, chemically assembled through a “click” synthesis. By reviewing concrete examples, we want to provide the reader with the insight that the application of click and bioorthogonal chemistry in the TDP field may be a winning combination.

Advancing cell-membrane-permeable and/or bioactive small-molecule ligands specifically binding to RNA structures may provide powerful tools to understand further RNA biology in live cells and facilitate the investigation in the cutting-edge research areas of fluorescence live-cell imaging, chemical biology and drug discovery.

Abstract

RNA structures, including those formed from coding and noncoding RNAs, alternative to protein-based drug targets, could be a promising target of small molecules for drug discovery against various human diseases, particularly in anticancer, antibacterial and antivirus development. The normal cellular activity of cells is critically dependent on the function of various RNA molecules generated from DNA transcription. Moreover, many studies support that mRNA-targeting small molecules may regulate the synthesis of disease-related proteins via the non-covalent mRNA-ligand interactions that do not involve gene modification. RNA-ligand interaction is thus an attractive approach to address the challenge of “undruggable” proteins in drug discovery because the intracellular activity of these proteins is hard to be suppressed with small molecule ligands. We selectively surveyed a specific area of RNA structure-selective small molecule ligands in fluorescence live cell imaging and drug discovery because the area was currently underexplored. This state-of-the-art review thus mainly focuses on the research published within the past three years and aims to provide the most recent information on this research area; hopefully, it could be complementary to the previously reported reviews and give new insights into the future development on RNA-specific small molecule ligands for live cell imaging and drug discovery.