William D. Lubell’s research while affiliated with University of Quebec in Montreal and other places

Neglected tropical diseases caused by trypanosomatid parasites such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi present a major public healthcare issue due in part to emerging resistance. Exploring multiple targeting ligands, conjugates composed of analogs from the ribosomal inhibitor anisomycin and glycosomal inhibitory almiramide peptides were made and shown to be inactive compared to the parent components. On the other hand, attachment of walkynyl chains characteristic of the lipid tails of anti-parasitic peptides to the p-position of anisomycin, gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant Leishmania strains. Cryo-electron microscopy revealed that the O-propargyl anisomycin analog bound similarly to the highly conserved peptidyl transferase center of the ribosome as the parent inhibitor. Thermal proteomic profiling and gene ontology analysis demonstrated that O-propargyl anisomycin exhibited a broader mode of action including activity against glycosome-associated proteins. Structure-activity study has revealed the utility of alkynyl substituents for improving antiparasitic activity against resistant strains by enlarging mode of action paving the way towards novel therapy against trypanosomatid infections.

A revolution in peptide production arrived from the innovation of carboxylate to amine C ‐ to N ‐direction solid‐phase synthesis. This cornerstone of modern peptide science has enabled multiple academic and industrial applications; however, the process of C ‐ to N ‐solid phase peptide synthesis (C‐N‐SPPS) has extreme process mass intensity and poor atom economy. Notably, C‐N‐SPPS relies upon the use of atom‐intensive protecting groups, such as the fluorenylmethyloxycarbonyl (Fmoc) protection and wasteful excess of protected amino acids and coupling agents. On the other hand, peptide synthesis in the amine to carboxylate N ‐ to C ‐direction offers potential to minimize protection and may arguably enable more efficient means for manufacturing peptides. For example, efficient amide bond formation in the N ‐ to C ‐direction has been accomplished using methods employing thioesters, vinyl esters, and transamidation to achieve peptide synthesis with minimal epimerization. This review aims to provide an overview of N ‐ to C ‐peptide synthesis indicating advantages in taking this avenue for sustainable peptide production.

Macrophage mitochondrial dysfunction, caused by oxidative stress, has been proposed as an essential event in the progression of chronic inflammation diseases, such as atherosclerosis. The cluster of differentiation-36 (CD36) and lectin-like oxLDL receptor-1 (LOX-1) scavenger receptors mediate macrophage uptake of oxidized low-density lipoprotein (oxLDL), which contributes to mitochondrial dysfunction by sustained production of mitochondrial reactive oxygen species (mtROS), as well as membrane depolarization. In the present study, the antioxidant mechanisms of action of the selective synthetic azapeptide CD36 ligand MPE-298 have been revealed. After binding to CD36, MPE-298 was rapidly internalized by and simultaneously induced CD36 endocytosis through activation of the Lyn and Syk (spleen) tyrosine kinases. Within this internalized complex, MPE-298 inhibited oxLDL/LOX-1-induced chemokine ligand 2 (CCL2) secretion, abolished the production of mtROS, and prevented mitochondrial membrane potential depolarization in macrophages. This occurred through the inhibition of the multiple-component enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) by oxLDL-activated LOX-1, which was further supported by the reduced recruitment of the p47phox subunit and small GTPase (Rac) 1/2/3 into the plasma membrane. A new mechanism for alleviating oxLDL-induced oxidative stress and inflammation in macrophages is highlighted using the CD36 ligand MPE-298.

APP E693Q transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of Aβ (NFA-Aβ) and APP α-carboxy terminal fragments. The APP E693Q mutation disrupts amyloid fibril formation, and no plaques develop in these mice. In the current study, the aging-related accumulation of NFA-Aβ in APP E693Q mice was revealed by A11 immunohistochemistry and NFA-Ab-detecting cyclic D,L-α-peptide-FITC microscopy. The presynaptic termini of APP E693Q mice developed aging-related physiological abnormalities in post-tetanic potentiation, synaptic fatigue, and synaptic vesicle replenishment. Single-cell RNA sequencing showed that excitatory neurons exhibited the most altered transcriptomic profile, especially involving “protein translation” and “oxidative phosphorylation”. Direct measurements of electron transport chain catalysis revealed reduction in mitochondrial complex I activity in Dutch mice. Microglial transcript analysis revealed no evidence of inflammation. The incomplete clinical response to fibrillar Aβ immunodepletion in human patients may be attributable to residual NFA-Aβ that are undetectable by currently available biofluid or neuroimaging biomarkers. The depletion or neutralization of both fibrillar and NFA-Aβ may be needed for complete elimination of Aβ toxicity. Teaser APP E693Q “NFA-Aβ only” mice reveal clinically relevant mechanisms despite the absence of detectable inflammation

The advancement of peptide production was revolutionized by the introduction of solid-phase synthesis in the C- to N-direction, from carboxylate to amine. This foundational technique in modern peptide science has facilitated numerous academic and industrial applications. However, C- to N-solid-phase peptide synthesis (C-N-SPPS) is associated with high process mass intensity and poor atom economy. A major drawback of C-N-SPPS is its dependence on atom-intensive protecting groups, such as fluorenylmethyloxycarbonyl (Fmoc), along with the excessive use of protected amino acids and coupling reagents. In contrast, synthesizing peptides in the N- to C-direction, from amine to carboxylate, presents an opportunity to reduce reliance on protective strategies and could offer a more efficient approach to peptide manufacturing. Notably, effective amide bond formation in the N- to C-direction has been achieved through techniques involving thioesters, vinyl esters, and transamidation, allowing for peptide synthesis with minimal epimerization. This review explores N- to C-peptide synthesis, highlighting its advantages as a more sustainable alternative for peptide production.

The Front Cover illustrates the numerous and major strategies developed for the sustainable total synthesis of natural products, while shedding light on the use of readily available chiral pools, such as (−)-sclareol, as a key synthesis approach. (−)-Sclareol has effectively enabled the synthesis of numerous complex natural products through diverse key intermediates and building blocks. Thus, (−)-sclareol has created shortcuts to access valuable bioactive molecules via greener and cost-effective routes. More information can be found in the Review by A. Selka, A. Abidli, G. Hanquet and co-workers (DOI: 10.1002/ejoc.202400983). Cover designed by A. Abidli.

The advancement of peptide production was revolutionized by the introduction of solid-phase synthesis in the C- to N-direction, from carboxylate to amine. This foundational technique in modern peptide science has facilitated numerous academic and industrial applications. However, C- to N-solid-phase peptide synthesis (C-N-SPPS) is associated with high process mass intensity and poor atom economy. A major drawback of C-N-SPPS is its dependence on atom-intensive protecting groups, such as fluorenylmethyloxycarbonyl (Fmoc), along with the excessive use of protected amino acids and coupling reagents. In contrast, synthesizing peptides in the N- to C-direction, from amine to carboxylate, presents an opportunity to reduce reliance on protective strategies and could offer a more efficient approach to peptide manufacturing. Notably, effective amide bond formation in the N- to C-direction has been achieved through techniques involving thioesters, vinyl esters, and transamidation, allowing for peptide synthesis with minimal epimerization. This review explores N- to C-peptide synthesis, highlighting its advantages as a more sustainable alternative for peptide production.

Starting materials for sustainable total synthesis often come from the chiral pool: carbohydrates, cyclitols, amino acids, and terpenes. In the terpene family, (−)‐sclareol has served as a sustainable, readily available, and versatile chiral building block for the synthesis of numerous natural products. (−)‐Sclareol possesses a unique structure that has consequently promoted its integration as a core framework within various structurally complex and biologically active substances, including sesquiterpenoids, diterpenoids, and sesterterpenoids. (−)‐Sclareol has facilitated access to diverse synthetic key intermediates, promoting the sustainable synthesis of several natural products. Herein, a review is presented covering the recent trends in sustainable total syntheses and the application of chiral pool approaches with emphasis on the preparation of natural products through diverse routes employing (−)‐sclareol as chiral educt. Innovative catalytic and synthetic protocols using (−)‐sclareol are also analyzed and discussed.

Background Clinicopathological studies of Alzheimer’s disease (AD) have demonstrated that synaptic or neuronal loss and clinical cognitive decline do not reliably correlate with fibrillar amyloid burden. We created a transgenic mouse model overexpressing Dutch (E693Q) mutant human amyloid precursor protein (APP) driven by the pan‐neuronal Thy1 promoter. Accumulation of APP carboxyl‐terminal fragments was observed in the brains of these mice, which develop an impaired learning phenotype directly proportional to brain oAβ levels. Method Male and female TgAPPE693Q mice and wildtype controls were compared using learning behavioral studies, immunocytochemistry, transmission electron microscopy, electrophysiology, protofibril‐specific assays, and single cell RNA sequencing. Result Brain levels of nonfibrillar oAβ in Dutch mice were shown to increase aging‐dependently using A11 immunocytochemistry and FITC‐cyclic peptide (FITC‐CP‐2) microscopy. Two assays excluded the presence of protofibrils. Electrophysiological characterization of hippocampal synapses in Dutch and wildtype mice at ∼7 and ∼11 months revealed no change in basal excitatory transmission, consistent with normal density and morphology of mGluR2/3+ synapses in hippocampal CA1 of the same mice. One exception was increased postsynaptic density in non‐perforated mGluR‐2/3+ synapses in the Dutch mice. Functional characterization of the presynaptic terminal showed abnormalities in post‐tetanic potentiation, synaptic fatigue, and synaptic replenishment after depletion in Dutch mice. Single cell RNA‐seq to elucidate cell‐type specific transcriptional responses to oAβ revealed altered transcriptional profiles in multiple cell types. Unexpectedly, no obvious differences existed between profiles of microglia from Dutch compared to those from wildtype mice. Excitatory neurons showed the most altered profile which was associated with ‘protein translation’ and ‘oxidative phosphorylation’. Ultrastructural analysis of presynaptic mitochondria at excitatory synapses revealed fewer mitochondria in the presynaptic terminals of Dutch mice. Conclusion The profound learning behavior deficits in Dutch mice are associated with presynaptic functional deficits and mitochondrial abnormalities in excitatory neurons of the hippocampus. Nonfibrillar oAβ deposits were revealed by co‐localization of A11 immunoreactivity with FITC‐CP‐2 microscopy. Mice accumulating only oAβ may be especially useful for further characterization of the oligomer‐specific cyclic azaglycine PET tracer Lys (⁶⁴Cu/NOTA)¹]‐CP‐7 that shows robust PET signal from 44‐day‐old presymptomatic 5xFAD mice [Habashi, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2022].