Inhibition of HSP90 distinctively modulates the global phosphoproteome of Leishmania mexicana developmental stages

Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that plays a central role in the folding and maturation of a large array of client proteins. In the unicellular parasite Leishmania, the etiological agent of the neglected tropical disease leishmaniasis, treatment with HSP90 inhibitors leads to differentiation from promastigote to amastigote stage, resembling the effects of established environmental triggers, low pH and heat shock. This indicates a crucial role for HSP90 in the life cycle control of Leishmania. However, the underlying molecular mechanisms remain unknown. Using a combination of treatment with the classical HSP90 inhibitor tanespimycin, phosphoproteome enrichment, and tandem mass tag (TMT) labeling-based quantitative proteomic mass spectrometry (MS), we systematically characterized the perturbing effect of HSP90 inhibition on the global phosphoproteome of Leishmania mexicana across its life cycle stages and showed that the HSP90 inhibition causes substantially distinct molecular effects in promastigote and amastigote forms.While phosphorylation of HSP90 and its co-chaperone HSP70 was decreased in amastigote, the opposite effect was observed in promastigotes. Our results showed that kinase activity and microtubule motor activity are highly represented in the negatively affected phosphoproteins of the promastigotes, whereas ribosomal proteins, protein folding, and proton channel activity are preferentially enriched in the perturbed amastigote phosphoproteome. Additionally, cross-comparison of our results with HSP90 inhibition-affected RNA-binding proteins showed that RNA helicase domains were distinctively enriched among the upregulated amastigote phosphoproteins. In addition to providing robust identification and quantification of 1,833 phosphorylated proteins across three life cycle stages of L. mexicana, this study reveals the dramatically different ways the HSP90 inhibition stress modulates the phosphoproteome of the pathogenic amastigote and provides in-depth insight into the scope of selective molecular targeting in the therapeutically relevant amastigote stage

Navigating drug repurposing for Chagas disease: advances, challenges, and opportunities

Chagas disease is a vector-borne illness caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). It poses a significant public health burden, particularly in the poorest regions of Latin America. Currently, there is no available vaccine, and chemotherapy has been the traditional treatment for Chagas disease. However, the treatment options are limited to just two outdated medicines, nifurtimox and benznidazole, which have serious side effects and low efficacy, especially during the chronic phase of the disease. Collectively, this has led the World Health Organization to classify it as a neglected disease. To address this problem, new drug regimens are urgently needed. Drug repurposing, which involves the use of existing drugs already approved for the treatment of other diseases, represents an increasingly important option. This approach offers potential cost reduction in new drug discovery processes and can address pharmaceutical bottlenecks in the development of drugs for Chagas disease. In this review, we discuss the state-of-the-art of drug repurposing approaches, including combination therapy with existing drugs, to overcome the formidable challenges associated with treating Chagas disease. Organized by original therapeutic area, we describe significant recent advances, as well as the challenges in this field. In particular, we identify candidates that exhibit potential for heightened efficacy and reduced toxicity profiles with the ultimate objective of accelerating the development of new, safe, and effective treatments for Chagas disease

Editorial: The evolution in pharmacology of infectious diseases: 2022

This editorial offers an insightful examination and analysis of the significant advancements in the field of infectious diseases from 2022 to 2023, specifically focusing on how these developments have transformed our approaches to combating such diseases. At the heart of this exploration is an overview of 15 pivotal articles featured in our Research Topic. These articles, contributed by 120 distinguished experts worldwide, represent a critical blend of knowledge, combining a range of expert insights and discoveries

Convenient Synthesis of the Immunogenic Glycolipid BbGL1

A simple and efficient method to synthesize the immunogenic glycolipid BbGL1 is introduced. Two simple steps were required to obtain the desired product in good yield. First, a highly efficient glycosylation of cholesterol using galactosyl trichloroacetimidate as a donor was performed to produce cholesteryl--D-galactoside. Finally, an efficient palmitoylation on the C6–OH of the galactose of the synthesized saponin using sym-collidine and acyl chloride under microwave heating that produced BbGL1 in good yield. The procedure is a convenient and cheaper alternative to the reported procedures allowing a rapid preparation of multiple analogs and conjugates

Navigating drug repurposing for Chagas disease: advances, challenges, and opportunities

Chagas disease is a vector-borne illness caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). It poses a significant public health burden, particularly in the poorest regions of Latin America. Currently, there is no available vaccine, and chemotherapy has been the traditional treatment for Chagas disease. However, the treatment options are limited to just two outdated medicines, nifurtimox and benznidazole, which have serious side effects and low efficacy, especially during the chronic phase of the disease. Collectively, this has led the World Health Organization to classify it as a neglected disease. To address this problem, new drug regimens are urgently needed. Drug repurposing, which involves the use of existing drugs already approved for the treatment of other diseases, represents an increasingly important option. This approach offers potential cost reduction in new drug discovery processes and can address pharmaceutical bottlenecks in the development of drugs for Chagas disease. In this review, we discuss the state-of-the-art of drug repurposing approaches, including combination therapy with existing drugs, to overcome the formidable challenges associated with treating Chagas disease. Organized by original therapeutic area, we describe significant recent advances, as well as the challenges in this field. In particular, we identify candidates that exhibit potential for heightened efficacy and reduced toxicity profiles with the ultimate objective of accelerating the development of new, safe, and effective treatments for Chagas disease

Repositioning Salirasib as New Antimalarial Agent

The antiplasmodial activity assay was performed using a simple, high-sensitivity methodology based on nanoluciferase (nLuc)-transfected P. falciparum parasites. The results showed that some of the analogs were active at low micromolar concentration. The most potent member of the series has S-farnesyl and the triazole moiety substituted with methyl-naphtyl. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indexes, being promising candidates for future antimalarial drugs development. Our results provide structure-activity relationship data for the design of new antimalarial drugs. </p

Lipophilic modification of Salirasib modulate the antiproliferative and antimigratory activity.

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. Although different salirasib derivatives have been reported, the isoprenyl tail has not been modified. In this study, we used a series of synthetic salirasib analogues with lipophilic thioether modifications, including those with or without a 1,2,3-triazole linker, and tested their antiproliferative activity against six different solid tumor cell lines. We carried out a combination of bioassay, cheminformatics, and in silico ADME-Tox to identify new potent analogues. SAR analysis revealed structural and physicochemical features that enhance antiproliferative activity. Analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, we identified three compounds with superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behaviour of the collection on migration and invasion, the key processes in tumor metastasis, were also studied. Three analogs with specific antimigratory activity were identified with differential structural features. The combination of the antiproliferative and antimigratory results prompts to propose that the modification on the thiol aliphatic/prenyl substituents can modulate the activity. Our findings provide valuable insight on the lipophilic salirasib analogues with enhanced antiproliferative activity against solid tumor cell lines. Also, we have been able to identify analogues with specific antimigratory activity that could be the starting points on the development of new antimetastatic agents

Stabilization and detection of hydrophylloquinone as di- O -methyl derivative

Phylloquinone is a redox active naphthoquinone involved in electron transport in plants. The function of this reduced form remains unclear due to its instability, which has precluded detection. Herein, a simple method that permits the stabilization of the reduced form of phylloquinone by di-O-methylation and HPLC detection is described