Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation.

The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro.

Discovery of a new eugenol-benznidazole hybrid active against different evolutive stages of Trypanosoma cruzi.

Chagas disease (CD) is a life-threatening illness caused by the protozoan Trypanosoma cruzi and there are only two drugs currently available for pharmacotherapy of this neglected infection (benznidazole and nifurtimox). Their limited efficacy in chronic phase of the disease, problems of toxicity and the growing resistance by the protozoan are directly associated to high rates of drug discontinuation by the patients. In the context of the search for new trypanocidal drug candidates, our group has been working with the chemical manipulation of eugenol to obtain new agents active against T.

Introducing CRAFT: The Center for Research and Advancement in Fragments and molecular Targets.

We introduce the Center for Research and Advancement in Fragments and Molecular Targets (CRAFT), a pioneering research center established in 2021 through a collaboration between the University of São Paulo (USP) and the Federal University of Goiás (UFG). CRAFT integrates fragment-based drug discovery (FBDD), artificial intelligence (AI), and structural biology to develop novel therapeutic strategies. We have created fragment and target libraries and utilize AI models to streamline the drug discovery process.

Optimization of HS-SPME/GC-MS Method for Determining Volatile Organic Compounds and Sensory Profile in Cocoa Honey from Different Cocoa Varieties ( L.).

This study aimed to develop an analytical method using HS-SPME/GC-MS to determine the volatile organic compound (VOC) profiles and evaluate the sensory attributes of cocoa honey from four cocoa varieties (CCN51, PS1319, SJ02, and Parazinho). Using a multivariate factorial experimental design, the HS-SPME/GC-MS method was optimized to determine the VOC profiles. Twenty previously trained tasters participated in the ranking descriptive analysis, while 108 consumers participated in the acceptance and purchase intention tests.

Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents.

An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1.

The importance of international collaborations in science and structural biology.

The Acta Cryst. F - Structural Biology Communications Editors explain how important international collaborations are in science and structural biology.

New 2-nitroimidazole-N-acylhydrazones, analogs of benznidazole, as anti-Trypanosoma cruzi agents.

Chagas disease is a neglected tropical parasitic disease caused by the protozoan Trypanosoma cruzi. Worldwide, an estimated 8 million people are infected with T. cruzi, causing more than 10,000 deaths per year.

Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2.

The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (DHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance.

Design and Synthesis of Novel 3-Nitro-1-1,2,4-triazole-1,2,3-triazole-1,4-disubstituted Analogs as Promising Antitrypanosomatid Agents: Evaluation of In Vitro Activity against Chagas Disease and Leishmaniasis.

A series of 28 compounds, 3-nitro-1-1,2,4-triazole, were synthesized by click-chemistry with diverse substitution patterns using medicinal chemistry approaches, such as bioisosterism, Craig-plot, and the Topliss set with excellent yields. Overall, the analogs demonstrated relevant in vitro antitrypanosomatid activity. Analog (R = 4-OCF-Ph, IC = 0.

Discovery of new piperaquine hybrid analogs linked by triazolopyrimidine and pyrazolopyrimidine scaffolds with antiplasmodial and transmission blocking activities.

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates.

Shaping the future of Acta Crystallographica F: unveiling our vision.

One of the Editors of Acta Cryst. F - Structural Biology Communications describes what the future holds for the journal.

Enlarged fistulotomy of the papilla as access to the biliary tract during ERCP.

Background: Demonstration of access to the bile duct through Enlarged Papillary Fistulotomy, a method different from conventional fistulotomy.

Aims: Demonstration of the EFP technique with dissection in layers of the papilla for accessing the common bile duct, its efficiency and safety, rescue of cases of failure in cannulation and cases of access failure by EFP in the first attempt, facilitating cannulation in the second attempt.

Methods: Cross-sectional study, with retrospective data collection from 2233 ERCP exams with 528 EFP procedures, analysis of success and complications.

Anti- Activity, Mutagenicity, Hepatocytotoxicity and Nitroreductase Enzyme Evaluation of 3-Nitrotriazole, 2-Nitroimidazole and Triazole Derivatives.

Chagas disease (CD), which is caused by and was discovered more than 100 years ago, remains the leading cause of death from parasitic diseases in the Americas. As a curative treatment is only available for the acute phase of CD, the search for new therapeutic options is urgent. In this study, nitroazole and azole compounds were synthesized and underwent molecular modeling, anti- evaluations and nitroreductase enzymatic assays.

The effects of lingual training: a systematic review with meta-analysis.

Purpose: To assess the effectiveness of myotherapy exercises in increasing tongue pressure and strength. A secondary aim was to analyze the exercise types, training parameters, and functional results.

Research Strategies: This systematic literature review was based on the Prisma protocol guidelines.

Design, synthesis and antitrypanosomatid activity of 2-nitroimidazole-3,5-disubstituted isoxazole compounds based on benznidazole.

Chagas disease and leishmaniasis are neglected diseases of high priority as a public health problem. Pharmacotherapy is based on the administration of a few drugs, which exhibit hazardous adverse effects and toxicity to the patients. Thus, the search for new antitrypanosomatid drugs is imperative to overcome the limitations of the treatments.

Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition.

Tuberculosis (TB) is a leading cause of death worldwide. TB represents a serious public health threat, and it is characterized by high transmission rates, prevalence in impoverished regions, and high co-infection rates with HIV. Moreover, the serious side effects of long-term treatment that decrease patient adherence, and the emergence of multi-resistant strains of Mycobacterium tuberculosis, the causing agent of TBs, pose several challenges for its eradication.

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions.

Repurposing of 5-nitrofuran-3,5-disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents.

Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease.

Trypanosoma cruzi nitroreductase: Structural features and interaction with biological membranes.

Due to its severe burden and geographic distribution, Chagas disease (CD) has a significant social and economic impact on low-income countries. Benznidazole and nifurtimox are currently the only drugs available for CD. These are prodrugs activated by reducing the nitro group, a reaction catalyzed by nitroreductase type I enzyme from Trypanosoma cruzi (TcNTR), with no homolog in the human host.

Rush order containment of critical drugs in ICUs.

The recent SARS CoV-02 pandemic has put enormous pressure on intensive care staff, making it imperative to relieve them of repetitive tasks with little added value such as drug replenishment. We propose a decision support system based on a hybrid policy to manage the inventory of critical drugs with low and intermittent demand at an Intensive Care Unit (ICU). Demand forecasting is at the heart of any inventory policy.