Environmental impacts of drugs against parasitic vector-borne diseases and the need to integrate sustainability into their development and use.

Background: The current scientific discourse on environmental impacts of veterinary medicines mostly focuses on ectoparasiticides. Meanwhile, the environmental impacts of widely prescribed drugs for the treatment of human and animal parasitic vector-borne diseases (PVBD) remain largely unexplored. There is thus a need for evidence-based information to support guidelines and protocols for sustainable One Health PVBD drug development and use, while promoting greener research practices.

Drugs for Vector-Borne Protozoal Diseases in a One Health Scenario. A European Perspective.

Vector-borne protozoal diseases (VBPD) represent an enormous health and economic burden, particularly in low- and middle-income countries. Their control requires integrated approaches that consider not only therapeutic interventions for affected human and animal populations but also preventive tools. Environmental contamination can lead to therapeutic ineffectiveness.

Automatic noise detection for ambulatory electrocardiogram in presence of ventricular arrhythmias through a machine learning approach.

Noise detection in ambulatory electrocardiography is investigated as a machine learning binary classification problem on a set of twelve noise indices. Ten of these noise indices are replicated from relevant scientific literature. Two novel noise indices are also introduced: the electrocardiogram derivative pattern similarity index (edp) and the number of inversions of the signal's slope over a minimum amplitude threshold (inv).

Biochemical characterization of the feedforward loop between CDK1 and FOXM1 in epidermal stem cells.

The complex network governing self-renewal in epidermal stem cells (EPSCs) is only partially defined. FOXM1 is one of the main players in this network, but the upstream signals regulating its activity remain to be elucidated. In this study, we identify cyclin-dependent kinase 1 (CDK1) as the principal kinase controlling FOXM1 activity in human primary keratinocytes.

Deciphering Host-Parasite Interplay in Infection through a One Health View of Proteomics Studies on Drug Resistance.

Recent efforts in the study of vector-borne parasitic diseases (VBPDs) have emphasized an increased consideration for preventing drug resistance and promoting the environmental safety of drugs, from the beginning of the drug discovery pipeline. The intensive use of the few available antileishmanial drugs has led to the spreading of hyper-resistant strains, resulting in a chronic burden of the disease. In the present work, we have investigated the biochemical mechanisms of resistance to antimonials, paromomycin, and miltefosine in three drug-resistant parasitic strains from human clinical isolates, using a whole-cell mass spectrometry proteomics approach.

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti- Agents.

Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles () and 2-guanidino benzimidazoles (), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS).

One Health.

Bertram and colleagues introduce the One Health concept, an interdisciplinary framework that aims to sustainably advance and safeguard the health of humans, animals, and the environment.

Assessing Environmental Risks during the Drug Development Process for Parasitic Vector-Borne Diseases: A Critical Reflection.

Parasitic vector-borne diseases (VBDs) represent nearly 20% of the global burden of infectious diseases. Moreover, the spread of VBDs is enhanced by global travel, urbanization, and climate change. Treatment of VBDs faces challenges due to limitations of existing drugs, as the potential for side effects in nontarget species raises significant environmental concerns.

The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents.

Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors.

Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery-Genetics Alliance Perspective.

The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying the target structural basis, its mutational progression, and the related biological significance to virus replication allows envisaging the development of better-targeted therapies in the context of COVID-19 epidemic and future coronavirus outbreaks. The identification of evolutionary patterns based solely on sequence information analysis for those targets can provide meaningful insights into the molecular basis of host-pathogen interactions and adaptation, leading to drug resistance phenomena.

Label-Free Mass Spectrometry Proteomics Reveals Different Pathways Modulated in THP-1 Cells Infected with Therapeutic Failure and Drug Resistance Clinical Isolates.

As the world is facing increasing difficulties to treat leishmaniasis with current therapies, deeper investigation into the molecular mechanisms responsible for both drug resistance and treatment failure (TF) is essential in drug discovery and development. So far, few available drugs cause severe side effects and have developed several resistance mechanisms. Drug resistance and TF parasite strains from clinical isolates may have acquired altered expression of proteins that characterize specific mechanisms leading to therapy inefficacy.

Serum Mass Spectrometry Proteomics and Protein Set Identification in Response to FOLFOX-4 in Drug-Resistant Ovarian Carcinoma.

Ovarian cancer is a highly lethal gynecological malignancy. Drug resistance rapidly occurs, and different therapeutic approaches are needed. So far, no biomarkers have been discovered to predict early response to therapies in the case of multi-treated ovarian cancer patients.

Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth.

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers.

Current Treatments to Control African Trypanosomiasis and One Health Perspective.

Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, . Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use.

Performance evaluation of a 3D-printed sharp-cut cyclone.

A sharp-cut cyclone with an aerodynamic cut-off diameter of 1 μm, when operated at a flow rate of 1 L min, was built by 3D-printing and tested against a metallic (aluminum) counterpart having the same design and dimensions. The penetration efficiency of both cyclones was experimentally determined using quasi-monodisperse aerosol particles having aerodynamic diameters from 100 nm to 2 μm. The aerodynamic cut-off diameter for both cyclones was very similar and in accordance with the expected design value.

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.

The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition.

Olaparib beyond progression compared with platinum chemotherapy after secondary cytoreductive surgery in patients with recurrent ovarian cancer: phase III randomized, open-label MITO 35b study, a project of the MITO-MANGO groups.

Background: Poly (ADP-ribose) polymerase inhibitors have transformed the management landscape for patients with ovarian cancer, demonstrating remarkable improvements in progression-free survival and overall survival. Unfortunately, most relapses are due to an acquired mechanism of resistance to these agents. We hypothesize that secondary cytoreductive surgery, removing resistant clones, might help to overcome the development of resistance to poly (ADP-ribose) polymerase inhibitors, prolonging their therapeutic effect.

Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library.

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect.

Sesquiterpene Lactones with Dual Inhibitory Activity against the Pteridine Reductase 1 and Dihydrofolate Reductase.

The parasite (. ) is responsible for human African trypanosomiasis (HAT) and the cattle disease "Nagana" which to this day cause severe medical and socio-economic issues for the affected areas in Africa. So far, most of the available treatment options are accompanied by harmful side effects and are constantly challenged by newly emerging drug resistances.

Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases.

Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both and parasites (pan-inhibitors), or from both PTR1 and DHFR-TS of the same parasite (dual inhibitors).

Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids.

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against and intracellular amastigotes, against and against different developmental stages of . The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure-activity relationships.

Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Pteridine Reductase and Dihydrofolate Reductase.

and parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to (), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required.