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.

1-1,2,3-triazol-1,4-naphthoquinone Derivatives: Novel Inhibitors Targeting Pyocyanin Biosynthesis for Infection Treatment Advances.

Background: This study investigates the potential of eleven 1H-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in infections.

Methods: A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders.

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.

The use of agitated saline as contrast agent in a contrast-enhanced cystosonography for detection of urinary bladder rupture in animal cadavers.

Objective: To determine the value of microbubble contrast cystosonography in the diagnosis of bladder rupture in animals.

Design: Prospective, method comparison study from November 2019 to October 2020.

Setting: University teaching hospital.

Comparison of radiographic methods for detecting radiolucent uroliths in dogs.

The purpose of this study was to evaluate and compare positive cystography techniques at 5%, 10%, and 20%, as well as three different double-contrast protocols for detecting radiolucent uroliths with a diameter of less than 3.0 mm in dogs. Six cadavers were used, one was selected at random to represent the negative control, and the others were submitted to urolith implantation in the bladder by urethral catheter.

Characterization of Doppler spectrum of hepatic veins in dogs with pulmonary hypertension.

Pulmonary hypertension (PH) triggers hemodynamic changes within the right heart, which may affect hepatic venous flow. The aims of this study were three-fold: to investigate, prospectively, the reliability of the hepatic vein Doppler waveform to diagnose and characterize the magnitude of PH in dogs; to evaluate whether a correlation exists between hepatic venous flow waves and the structural and functional characteristics of the right ventricle (RV); and to determine whether age, gender, body weight, heart rate (HR), heart rhythm and systolic blood pressure affect the hepatic venous waveform pattern. A cross-sectional observational study was carried out in 43 dogs with varying degrees of PH and a control group of 15 healthy dogs.

Unraveling the Cardiac Effects Induced by Carvacrol in Spontaneously Hypertensive Rats: Involvement of Transient Receptor Potential Melastatin Subfamily 4 and 7 Channels.

Accumulating evidence indicates that transient receptor potential (TRP) channels are involved in the pathophysiological process in the heart, and monoterpenes, such as carvacrol, are able to modulate these channels activity. In this article, our purpose was to evaluate the direct cardiac effect of carvacrol on the contractility of cardiomyocytes and isolated right atria from spontaneously hypertensive and Wistar Kyoto rats. In this way, in vitro experiments were used to evaluate the ventricular cardiomyocytes contractility and the Ca2+ transient measuring, in addition to heart rhythm in the right atria.

Window Collisions by Birds in Brazil: Epidemiologic Factors and Radiographic and Necropsy Assessments.

Birds are among the most visually proficient group of animals on the planet; however, their inability to visualize and discriminate translucent glass structures results in an extreme number of deaths worldwide from high-speed collisions. Despite reports of avian glass collisions in North America, only a few studies have been developed to understand this problem in South America, and none evaluated radiographic and postmortem findings. One hundred cadavers were examined radiographically and postmortem, and data from 186 collision reports were analyzed for seasonality (website and manual reports and cadavers).

Thermal shift assays of marine-derived fungal metabolites from MMERU 23 against pteridine reductase 1 and molecular dynamics studies.

Marine-derived fungi are a promising source of bioactive molecules, especially species from extreme habitats. Although several secondary metabolites such as meroterpenoids and alkaloids have been isolated from cultures of obtained from terrestrial habitats, there is no report on compounds isolated from marine-derived strains. Many metabolites isolated from marine-derived fungi exhibited a myriad of biological activities.

DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts.

Background: Dihydroorotate dehydrogenase (DHODH) has long been recognized as an important drug target for proliferative and parasitic diseases, including compounds that exhibit trypanocidal action and broad-spectrum antiviral activity. Despite numerous and successful efforts in structural and functional characterization of DHODHs, as well as in the development of inhibitors, DHODH hot spots remain largely unmapped and underexplored.

Objective: This review describes the tools that are currently available for the identification and characterization of hot spots in protein structures and how freely available webservers can be exploited to predict DHODH hot spots.

Druggable hot spots in trypanothione reductase: novel insights and opportunities for drug discovery revealed by DRUGpy.

Assessment of target druggability guided by search and characterization of hot spots is a pivotal step in early stages of drug-discovery. The raw output of FTMap provides the data to perform this task, but it relies on manual intervention to properly combine different sets of consensus sites, therefore allowing identification of hot spots and evaluation of strength, shape and distance among them. Thus, the user's previous experience on the target and the software has a direct impact on how data generated by FTMap server can be explored.

Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to PhzS.

The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit PhzS (PzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (- Kd = 18 µM and LE = 0.

Congenital Heart Disease in Dogs: A Retrospective Study of 95 Cases.

The aim of the study was to estimate the prevalence of congenital heart diseases in dogs attending 2 veterinary hospitals in Brazil and to identify possible associations between these conditions and epidemiological characteristics. A retrospective study was carried out in the cardiology sections of 2 veterinary hospitals during a period of 70 months from January 2012 and October 2017. Of a total of 6710 dogs that attended the cardiology sections of the hospitals, 109 congenital heart diseases were identified in 95 patients, representing a prevalence of 1.

Triazol-phenyl Antipyretic Derivatives Inhibit mPGES-1 mRNA Levels in LPS-Induced RAW 264.7 Macrophage Cells.

Background: Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) production, which plays an important role in the regulation of febrile response. In our previous work, ligand-based pharmacophore models, built with mPGES-1 inhibitors, were employed to identify a novel series of compounds that reduce the febrile response in rats.

Objectives: The study aimed to evaluate the mechanism of action of the most active compound (1).

Comparison of blind intubation and a smartphone-based endoscope-assisted intubation in rabbits.

Objective: To compare between blind and smartphone-based endoscope-assisted techniques for endotracheal intubation in rabbits.

Study Design: Prospective clinical study.

Animals: A total of 34 rabbits.

Inhibition of intracellular Ca mobilization and potassium channels activation are involved in the vasorelaxation induced by 7-hydroxycoumarin.

Coumarins exhibit a wide variety of biological effects, including activities in the cardiovascular system and the aim of this study was to evaluate the vascular therapeutic potential of 7-Hydroxicoumarin (7-HC). The vascular effects induced by 7-HC (0.001 μM-300 μM), were investigated by in vitro approaches using isometric tension measurements in rat superior mesenteric arteries and by in silico assays using Ligand-based analysis.

A novel scaffold to fight pyocyanin production: early steps to novel antivirulence drugs.

Although bacterial resistance is a growing concern worldwide, the development of antibacterial drugs has been steadily decreasing. One alternative to fight this issue relies on reducing the bacteria virulence without killing it. PhzS plays a pivotal role in pyocyanin production in .

Antileishmanial activity evaluation of thiazolidine-2,4-dione against Leishmania infantum and Leishmania braziliensis.

Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which makes the development of new drugs urgent. To achieve this goal, the integration of kinetic and DSF assays against parasitic validated targets, along with phenotypic assays, can help the identification and optimization of bioactive compounds.

Calycopterin, a major flavonoid from Marcetia latifolia, modulates virulence-related traits in Pseudomonas aeruginosa.

Although bacterial resistance is a worldwide growing concern, the development of bacteriostatic and bactericidal drugs has been decreasing in the last decade. Compounds that modulate the microorganism virulence, without killing it, have been considered promising alternatives to combat bacterial infections. However, most signaling pathways that regulate virulence are complex and not completely understood.

Structure-activity relationships and mechanism of action of tetragomycin derivatives as inhibitors of Staphylococcus aureus staphyloxanthin biosynthesis.

Despite the main strategy to overcome bacterial resistance has focused on the development of more potent antimicrobial agents, the evolutionary pressure caused by such drugs makes this strategy limited. Molecules that interfere with virulence factors appear as a promising alternative though, as they cause reduced selective pressure. As a matter of fact, staphyloxanthin biosynthesis inhibition (STXBI) has been pursued as promising strategy to reduce S.

Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) from .

Leishmaniasis is a tropical disease found in more than 90 countries. The drugs available to treat this disease have nonspecific action and high toxicity. In order to develop novel therapeutic alternatives to fight this ailment, pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHF-TS) have been targeted, once is auxotrophic for folates.

Reliability of smartphone-based radiographic interpretation for evaluating cardiogenic pulmonary oedema in dogs.

Objective: To compare the accuracy of radiological diagnosis of cardiogenic pulmonary oedema in dogs using two viewing platforms.

Material And Methods: A retrospective cross-sectional study including cases admitted between January 2012 and December 2016. Thoracic radiographs from 121 dogs with and without cardiogenic pulmonary oedema were included.

Structure-based Druggability Assessment of Anti-virulence Targets from Pseudomonas aeruginosa.

Antimicrobial Resistance (AMR) represents a serious threat to health and the global economy. However, interest in antibacterial drug development has decreased substantially in recent decades. Meanwhile, anti-virulence drug development has emerged as an attractive alternative to fight AMR.