New metalloantibiotics: With the rise and spread of multidrug-resistant fungal pathogens, new drugs are urgently needed. In this work, new ruthenium- and palladium-based compounds with promising antifungal properties are reported.

Abstract

Infections associated with antimicrobial resistance (AMR) are poised to become the leading cause of death in the next few decades, a scenario that can be ascribed to two phenomena: antibiotic over-prescription and a lack of antibiotic drug development. The crowd-sourced initiative Community for Open Antimicrobial Drug Discovery (CO-ADD) has been testing research compounds contributed by researchers around the world to find new antimicrobials to combat AMR, and during this campaign has found that metallodrugs might be a promising, yet untapped source. To this end, we submitted 18 Pd^II− and Ru^II−pyridyl−1,2,3-triazolyl complexes that were developed as catalysts to assess their antimicrobial properties. It was found that the Pd complexes, especially Pd1, possessed potent antifungal activity with MICs between 0.06 and 0.125 μg mL⁻¹ against Candida glabrata. The in-vitro studies were extended to in-vivo studies in Galleria mellonella larvae, where it was established that the compounds were nontoxic. Here, we effectively demonstrate the potential of Pd^II−pyta complexes as antifungal agents.

This review paper examines immunotherapeutic and chemical drug candidates for Alzheimer's disease (AD) and suggests a drug discovery strategy to overcome the obstacles in chemical-driven drug discovery. We evaluate the prospects of an alternative approach in chemical-based drug development that will help bypass the difficulties of chemical-driven drug development, capable of amyloid clearance just as immunotherapy candidates.

Abstract

Alzheimer's disease (AD) is the most prevalent cause of dementia and has become a health concern worldwide urging for an effective therapeutic. The amyloid hypothesis, currently the most pursued basis of AD drug discovery, points the cause of AD to abnormal production and ineffective removal of pathogenic aggregated amyloid-β (Aβ). AD therapeutic research has been focused on targeting different species of Aβ in the amyloidogenic process to control Aβ content and recover cognitive decline. Among the different processes targeted, the clearance mechanism has been found to be the most effective, supported by the recent clinical approval of an Aβ-targeting immunotherapeutic drug which significantly slowed cognitive decline. Although the current AD drug discovery field is extensively researching immunotherapeutic drugs, there are numerous properties of immunotherapy in need of improvements that could be overcome by an equally performing chemical drug. Here, we review chemical and immunotherapy drug candidates, based on their mechanism of modulating the amyloid cascade, selected from the AlzForum database. Through this review, we aim to summarize and evaluate the prospect of Aβ-targeting chemical drugs.

Pyrazines are ubiquitous in nature and biosynthesized by microorganisms, insects, and plants. Especially 3-alkyl-2-methoxypyrazines (MPs) play a key role as important aroma compounds in foods. Recently, in vivo feeding experiments with stable isotope labeled compounds revealed l-leucine and l-serine as important precursors for IBMP. This discovery gave evidence for a metabolic interface between the MP-biosynthesis and photorespiration.

Abstract

Pyrazines are ubiquitous in nature – biosynthesized by microorganisms, insects, and plants. Due to their great structural diversity, they own manifold biological functions. Alkyl- and alkoxypyrazines for instance play a key role as semiochemicals, but also as important aroma compounds in foods. Especially 3-alkyl-2-methoxypyrazines (MPs) have been of great research interest. MPs are associated with green and earthy attributes. They are responsible for the distinctive aroma properties of numerous vegetables. Moreover, they have a strong influence on the aroma of wines, in which they are primarily grape-derived. Over the years various methods have been developed and implemented to analyse the distribution of MPs in plants. In addition, the biosynthetic pathway of MPs has always been of particular interest. Different pathways and precursors have been proposed and controversially discussed in the literature. While the identification of genes encoding O-methyltransferases gave important insights into the last step of MP-biosynthesis, earlier biosynthetic steps and precursors remained unknown. It was not until 2022 that in vivo feeding experiments with stable isotope labeled compounds revealed l-leucine and l-serine as important precursors for IBMP. This discovery gave evidence for a metabolic interface between the MP-biosynthesis and photorespiration.

This review highlights the role of biotechnology and computational methods in sustainable fragrance production, focusing on fermentation, biocatalysis, and genetic engineering.

Abstract

Current environmental and safety considerations urge innovation to address the need for sustainable high-value chemicals that are embraced by consumers. This review discusses the concept of sustainable fragrances, as high-value, everyday and everywhere chemicals. Current and emerging technologies represent an opportunity to produce fragrances in an environmentally and socially responsible way. Biotechnology, including fermentation, biocatalysis, and genetic engineering, has the potential to reduce the environmental footprint of fragrance production while maintaining quality and consistency. Computational and in silico methods, including machine learning (ML), are also likely to augment the capabilities of sustainable fragrance production. Continued innovation and collaboration will be crucial to the future of sustainable fragrances, with a focus on developing novel sustainable ingredients, as well as ethical sourcing practices.

Dynamic covalent polymerization enables translating nucleic acid templates into synthetic precision polymers displaying sensitivity to pH and redox changes. In return, the templated polymers may serve as smart gene delivery vehicles. The overall process amounts to therapeutic nucleic acids fabricating their own delivery vector, thus mimicking the dynamic templated self-assembly of viral capsids and opening new avenues in gene therapies.

Abstract

Nucleic acids are information-rich and readily available biomolecules, which can be used to template the polymerization of synthetic macromolecules. Here, we highlight the control over the size, composition, and sequence one can nowadays obtain by using this methodology. We also highlight how templated processes exploiting dynamic covalent polymerization can, in return, result in therapeutic nucleic acids fabricating their own dynamic delivery vector – a biomimicking concept that can provide original solutions for gene therapies.

Pro-PROTAC, with precise and selective modulation within specific cell populations, would greatly enhance the target protein degradation process in a controllable manner. The development of such innovative chemistry holds significant promise for advancing the field of targeted protein degradation.

Abstract

PROTACs (Proteolysis-Targeting Chimeras) have emerged as a groundbreaking class of chemical tools that facilitate the degradation of target proteins by leveraging the ubiquitin-proteasome system (UPS). However, the effective utilization of PROTACs in chemical biology studies and therapeutics encounters significant challenges when it comes to achieving cell-selective protein degradation and in vivo applications. This review article aims to shed light on recent advancements in the development of Pro-PROTACs, which exhibit controlled protein degradation capabilities in response to external stimuli or disease-related endogenous biochemical signals. The article delves into the specific chemical strategies employed to regulate the interaction between PROTACs and E3 ubiquitin ligases or target proteins. These strategies enable spatial and temporal control over the protein degradation potential of Pro-PROTACs. Furthermore, the review summarizes recent investigations regarding the delivery of PROTACs using biodegradable nanoparticles for in vivo applications and targeted protein degradation. Such delivery systems hold great promise for enabling efficient and selective protein degradation in vivo. Lastly, the article provides a perspective on the future design of multifunctional PROTACs and their intracellular delivery mechanisms, with a particular focus on achieving cell-selective protein degradation.

Focal adhesion kinase (FAK) is an attractive cancer drug target. Here, we describe a medicinal chemistry campaign to develop a selective FAK inhibitor (BSJ-04-175) and PROTAC (BSJ-04-146). We show that BSJ-04-146 induces rapid and selective FAK degradation in cancer cells, degrades FAK in vivo, and displays improved biological activity compared to FAK inhibition.

Abstract

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small-molecule inhibition or degradation.

A DNA-based paclitaxel (PTX) and doxorubixin (DOX) delivery system was prepared, including Tn-PTX with different length of ssDNA tail (polythymine, Tn) and the DNA origami-based PTX\DOX\MUC-1 aptamer nanobarrel. In addition, the drug release, cytotoxicity and cellular uptake behaviors of Tn-PTX and nanobarrel in vitro were evaluated.

Abstract

Co-delivery of anticancer drugs and target agents by endogenous materials is an inevitable approach towards targeted and synergistic therapy. Employing DNA base pair complementarities, DNA nanotechnology exploits a unique nanostructuring method and has demonstrated its capacity for nanoscale positioning and templated assembly. Moreover, the water solubility, biocompatibility, and modifiability render DNA structure suitable candidate for drug delivery applications. We here report single-stranded DNA tail conjugated antitumor drug paclitaxel (PTX), and the co-delivery of PTX, doxorubicin and targeting agent mucin 1 (MUC-1) aptamer on a DNA nanobarrel carrier. We investigated the effect of tail lengths on drug release efficiencies and dual drug codelivery-enabled cytotoxicity. Owing to the rapidly developing field of structural DNA nanotechnology, functional DNA-based drug delivery is promising to achieve clinical therapeutic applications.

Doin’ the right thing: Fidaxomicin (Fdx) constitutes a potent antibiotic with a formidable power against menacing bacteria like Clostridioides difficile and Mycobacterium tuberculosis. Chemical synthesis of different substitution patterns on fidaxomicin resulted in specific antibiotic activity across species.

Abstract

Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram-positive bacteria such as Mycobacterium tuberculosis. Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well-studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram-negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho-methyl Fdx also exhibited activity against the Gram-negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next-generation fidaxomicin antibiotics.

NSD2 is a histone methyltransferase predominantly catalyzing di-methylation of histone H3 on lysine K36. Increased NSD2 activity due to mutations or fusion-events affecting the gene encoding NSD2 is considered an oncogenic event and a driver in various cancers, including multiple myelomas carrying t(4;14) chromosomal translocations and acute lymphoblastic leukemia's expressing the hyperactive NSD2 mutant E1099K. Using DNA-encoded libraries, we have identified small molecule ligands that selectively and potently bind to the PWWP1 domain of NSD2, inhibit NSD2 binding to H3K36me2-bearing nucleosomes, but do not inhibit the methyltransferase activity. The ligands were subsequently converted to selective VHL1-recruiting NSD2 degraders and by using one of the most efficacious degraders in cell lines, we show that its leads to NSD2 degradation, decrease in K3K36me2 levels and inhibition of cell proliferation.