Alternative Mechanisms Of Action Research Articles

Synthesis and preclinical evaluation of [11C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor

BackgroundMutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium.Results2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [11C]EAI045 was synthesized using [11C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [11C]CO2 production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [3H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [11C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [3H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [11C]EAI045.ConclusionsEAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [11C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [11C]EAI045 in vivo or [3H]EAI045 in vitro in H1975 xenografts and cells.

Tartaric acid new derivatives as prospective and safe alternative to antimicrobials for food products packing

Introduction: Multi-drug resistance of pathogens and food spoilage bacteria is one of the most prevalent problems in contemporary science because the microbial adaptation potential is permanently being stimulated by the excessive antibiotic usage by mankind. In this research, seven new derivatives of tartaric acid (TA) were studied. Their high activity against the multi-drug resistant bacteria and the biodegradation potential by soil microflora was demonstrated.Objective: Based on multiple literature data about aldaric acids antimicrobial properties, for combating pan-drug and especially multi-drug resistant pathogenic microbes, natural L-tartaric acid was target-derivatized by cyclohexyl-, phenyl-, benzyl- and ethanolamine- functional groups into complex amino salts and cyclic imides, which have demonstrated the significant bactericidal and bacteriostatic activity against the spoilage agent bacteria, as well as phytopathogenic and human opportunistic pathogens.Results: In vitro analyses of TA ethanolamine- benzyl-, cyclohexyl- and phenyl- imides and complex amino salts have shown that the mentioned substances are highly active agents for combating multi-drug resistant Gram-positive and Gram-negative pathogens and food spoilage microbes, such as: Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Klebsiella pneumonia, Salmonella enteritidis, Staphylococcus aureus, etc. These compounds are biodegradable by P. chlororaphis group non-pathogenic bacteria and their resistance is ensured by genes of nucleoid as well as are not transmitted by plasmids. In silico analyses have demonstrated their alternative mechanism of action. Conclusions: The results suggest that TA new derivatives can be potentially recommended as safe alternative antimicrobials for food packaging.Keywords: tartaric acid imides, tartaric acid complex aminosalts, spoilage microorganisms, antimicrobial activity, multi-drug resistance.

Structure-based design of SARS-CoV-2 papain-like protease inhibitors

The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PLpro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PLpro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PLpro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PLpro) with two potent inhibitors, Jun9722 and Jun9843. Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PLpro inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.

Advances in Therapies Targeting Inhibitory Checkpoint Receptors: TIGIT, LAG-3, and Beyond

Progress in our understanding of how tumor cells co-opt immune checkpoint receptor (ICR) regulation of the immune response to suppress T cell function and how these proteins interact in the tumor microenvironment has resulted in the development of a plethora of therapeutic ICR monoclonal antibodies. While anti-CTLA-4 and anti-PD-1/PD-L1 therapies have provided meaningful clinical benefit in patients with certain cancers, many patients either do not respond or experience disease progression. As such, dual blockade of PD-1/PD-L1 and ICRs with alternative mechanisms of action has the potential to improve outcomes in patients with cancer. In this review, we focus on the biology of and clinical investigations into two promising ICR targets: LAG-3 and TIGIT. The data suggest that blockade of these ICRs in combination with PD-1/PD-L1 in immune-sensitive tumors could enhance anti-PD-1 efficacy without increased toxicity, facilitate combinations with standard-of-care therapies, and extend treatment benefit to more patients.

Receptor specific mechanisms underlying psychedelic effects on affective behaviors

AbstractBackgroundAlzheimer’s Disease (AD) patients experience affective symptoms. Conventional therapies to address affective symptoms have limited efficacy in AD, alternative options, like psychedelics, have received interest. Psychedelics work through serotonergic pathways ‐ a neuromodulatory system with dysfunction in AD ‐mechanisms underlying behavioral changes and potential efficacy of their use are unknown. Evaluation of mechanisms underlying behavioral effects is needed to determine their potential as interventions. Psychedelics act through serotonin receptors, not serotonin re‐uptake inhibition characteristic of typical antidepressants. We investigate psychedelics’ mechanism of action as a potential effector of hedonic tone to assess its potential use for affective symptoms in AD.MethodWT mice were subject to one of three paradigms: (1) a 10‐day social defeat stress (SDS); (2) an injection of 2,5‐Dimethoxy‐4‐iodoamphetamine (DOI); or (3) SDS with DOI. SDS was used instead of an AD proteinopathy model to induce effects like anhedonia. Afterwards, mice underwent behavioral tests to evaluate compulsivity and affect. An additional group will receive DOI +serotonin receptor antagonistsResultFirst, SDS increased time spent in closed arms of the elevated plus maze (EPM; p = 0.0068) indicating an increase in anxiety. It also increased nest shredding (NST; p = 0.206), indicating an increase in compulsivity.Secondly, an injection of DOI decreased time spent in closed arms (p = 0.0151) indicating decrease in anxiety, and decreased nest shredding (p = 0.0325) indicating a decrease in compulsivity.Lastly, we expect that DOI will decrease anxiety and compulsivity. We expect to find the inverse to be true in mice that receive DOI +antagonist.ConclusionWe are showing that a traumatic stressor, like that a human might experience pre‐AD, induces potentially maladaptive affective behavioral changes. Here, we’ve demonstrated that psychedelics can act to recover affective dysfunction by activation of serotonin receptors. Because of degeneration of key serotonergic nuclei in AD, the use of serotonin reuptake inhibitors has limited efficacy for addressing symptoms like depression. Psychedelics may offer improved outcomes for AD patients in this regard due to its alternative mechanism of action. Further work to evaluate the efficacy of psychedelics in animal models more closely approximating AD‐type changes in serotonergic systems will help refine this understanding and guide potential clinical applications.

The Role of Anesthesia in Pain Management: Advancements in Perioperative Analgesia

This paper examines in detail the important role of anesthesia in perioperative pain management, focusing on recent advances in perioperative analgesia on. This paper examines the fundamental relationship between anesthesia and analgesia, with particular emphasis on recent innovations in surgical analgesic techniques. This study aims to elucidate the evolving panorama of anesthesia in surgical settings, losing light on how those trends are improving ache manipulate for sufferers. This paper uses a rigorous research approach including an extensive literature review and empirical data collection to support the findings. This study demonstrates the significant impact of modern anesthesia, including important insights into alternative mechanisms of action and effectiveness, for healthcare professionals and researchers in this field gain valuable insights. By addressing these factors, this paper seeks to inform the understanding of how anesthesia plays an important role in improving the perioperative experience of patients by improving pain and to make progress. Keywords: Anesthesia, Pain Management, perioperative Analgesia, Healthcare professionals, Patients care.

A Phase II Study of Loncastuximab Tesirine As Consolidation Strategy in Patients with LBCL in PR at Day 30 after CAR T-Cell Therapy

Background and Significance. Approximately 30% of patients with large B-cell lymphoma (LBCL) treated with autologous anti-CD19 CAR T-cell therapy (CART) achieve a partial response (PR) on day 30 (D30) assessment. Of those, up to 30% may spontaneously convert to a complete response (CR) during subsequent re-staging. While up to 70% of patients with D30 PR eventually progress, reliable biomarkers that help identify patients at risk are not yet available, and the current standard approach is close monitoring. CD19 expression is retained in most tumors of patients who relapse or progress after CART. Potential reasons for resistance in these tumors include T-cell dysfunction and tumor intrinsic mechanisms that resist T-cell mediated killing. Therefore, targeting such tumors with agents that have an alternative mechanism of action is likely to improve outcomes. To this regard, loncastuximab tesirine (Lonca) is an anti-CD19 antibody conjugated to a cytotoxic pyrrolobenzodiazepine dimer approved by the FDA for LBCL patients who relapse after at least 2 lines of systemic therapy. In the phase 2 LOTIS-2 study, Lonca was associated with an overall response rate of 48% and a CR rate of 24%, and included patients previously treated with CART. Grade 3-4 adverse events were observed in less than one third of patients, and were mainly represented by myelosuppression, skin toxicity and isolated GGT elevation. Study Design and Methods. This is a phase 2 single center study to investigate the safety and efficacy of Lonca as a consolidation strategy for LBCL patients with D30 PR after standard of care CART (NCT05464719). Patients with LBCL, including diffuse large B-cell lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed follicular lymphoma, treated with standard of care CART (in second line and beyond) and with PET-CT evidence of D30 PR are eligible for this study. Patients with absolute neutrophil count < 1000/uL and/or platelet count < 50,000/uL, and those with previous or active central nervous system involvement are excluded. Tissue biopsy for confirmation of PR will be performed; CD19 expression is not required for eligibility. Lonca is administered intravenously, on day 1 of a 21-day cycle, at a dose of 150 mcg/kg for the first 2 cycles, and 75 mcg/kg subsequently, for a total of 6 cycles. Response is assessed by PET-CT, according to 2014 Lugano criteria, after 3 cycles and at the end of treatment. The primary objective is efficacy, measured as conversion from D30 PR to CR. Using a one arm binomial exact test, hypothesizing an increase in conversion rate to CR from 30% to 60%, a sample size of 30 patients has a 90% power to observe a significant difference, with an alpha error of 0.05; a futility analysis, based on efficacy and toxicity, will be performed after the first 10 patients are treated. Secondary objectives are safety and other measurements of efficacy, including duration of CR. Exploratory objectives include identification of biomarkers of response and resistance. Peripheral blood samples will be collected pre-treatment, after 3 cycles, post-treatment and at time of progression, as well as collection of a pre-treatment tissue biopsy and at time of progression. Blood and tissue samples will be analyzed by multi-parameter flow cytometry and hiplex imaging assays (Phenocycler-Fusion/CODEX) to identify immune signatures of response and resistance to Lonca, and to assess CAR T-cell persistence; blood samples will be analyzed by CAPP-Seq to measure minimal residual disease. Finally, total metabolic tumor volume will be assessed on pre-treatment PET-CT scans, and association with response to consolidation therapy will be analyzed.

Time to progression of disease and outcomes with second-line BTK inhibitors in relapsed/refractory mantle cell lymphoma

AbstractTime to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton’s tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.

Abstract 4024: Overcoming ALK resistance with covalent cysteine-reactive inhibitors in lung cancer

Abstract The EML4-ALK fusion gene is the main oncogenic driver in 5% of non-small cell lung cancer and has been effectively targeted using ALK-specific tyrosine kinase inhibitors. While survival rates have improved steadily with each new generation of ALK TKI, resistance generally develops, including second site ALK kinase mutations as well as by-pass track activation. Since almost all anti-ALK approaches have focused on kinase domain inhibition, we sought to develop novel inhibitors with alternative mechanisms of action against ALK to overcome current drug resistance. Cysteine-reactive small molecule drugs may enable new mechanisms of target inhibition, and clinically successful examples of recent FDA-approved drugs in NSCLC include afatinib, osimertinib, sotorasib, and adagrasib.We aimed to explore and uncover novel cysteine-reactive covalent inhibitors of EML4-ALK. Using cysteine druggability mapping (CDM), a proteome-wide mass spectrometry target engagement assay, we first determined the landscape of reactive cysteines in ALK-positive cell lines and identified various targetable cysteines within the MAPK pathway and within the EML4-ALK fusion protein itself. To identify small molecules that modulate ALK activation, degradation, and downstream signaling, we conducted a high-content phosphorylated protein screen by testing 4,400 reactive cysteine compounds and found 20 potential hits that impacted ALK phosphorylation or expression. Using proteomic analysis, we have determined the comparative specificity of these compounds, and have ranked them based on p-ALK reduction efficiency and on their off-target binding patterns. We have initiated hit-to-lead development on a compound that binds to the EML4 portion of the fusion and we are performing a detailed analysis of its mechanism of action. To further optimize the potency of the compound, we designed, synthesized, and are testing several hundred analog compounds. By applying the hit compounds from the screen in ALK TKI-resistant models, we will be able to evaluate the ability of these compounds to overcome ALK resistance. To our knowledge, we have identified the first EML4-ALK covalent binder targeting the EML4 domain. Using the unique mechanism of action of the current ALK kinase inhibitor, we have uncovered a potential compound to overcome ALK resistance. Citation Format: Diane Yang, Stefan Harry, Edwin Zhang, Zavontae Oppong-Holmes, Alexander Daniel Carlin, Wenxin Yang, Abigail Smith, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate. Overcoming ALK resistance with covalent cysteine-reactive inhibitors in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4024.

ASSOCIATION OF CYCLING BETWEEN ANTI-TNFS VERSUS SWITCHING TO USTEKINUMAB WITH MEDICATION PERSISTENCE IN ANTI-TNF EXPERIENCED PATIENTS WITH CROHN'S DISEASE

Anti-tumor necrosis factor inhibitors (anti-TNFs) are biologics commonly used for the treatment of Crohn’s disease (CD). Over time, patients may require adjustment to anti-TNF therapy, including cycling to a different anti-TNF or switching to a biologic with an alternate mechanism of action. Choice of a treatment strategy could be key to managing symptoms on a sustained basis. This study aimed to compare real-world persistence among patients with CD who cycled to another anti-TNF agent or switched to ustekinumab.

Antiviral Effect of Ginsenosides rk1 against Influenza a Virus Infection by Targeting the Hemagglutinin 1-Mediated Virus Attachment

Influenza A virus (IAV) infections have been a serious hazard to public health everywhere. With the growing concern of drug-resistant IAV strains, there is an urgent need for novel anti-IAV medications, especially those with alternative mechanisms of action. Hemagglutinin (HA), an IAV glycoprotein, plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a good target for developing anti-IAV drugs. Panax ginseng is a widely used herb in traditional medicine with extensive biological effects in various disease models, and its extract was reported to show protection in IAV-infected mice. However, the main effective anti-IAV constituents in panax ginseng remain unclear. Here, we report that ginsenoside rk1 (G-rk1) and G-rg5, out of the 23 screened ginsenosides, exhibit significant antiviral effects against 3 different IAV subtypes (H1N1, H5N1, and H3N2) in vitro. Mechanistically, G-rk1 blocked IAV binding to sialic acid in a hemagglutination inhibition (HAI) assay and an indirect ELISA assay; more importantly, we showed that G-rk1 interacted with HA1 in a dose-dependent manner in a surface plasmon resonance (SPR) analysis. Furthermore, G-rk1 treatment by intranasal inoculation effectively reduced the weight loss and mortality of mice challenged with a lethal dose of influenza virus A/Puerto Rico/8/34 (PR8). In conclusion, our findings reveal for the first time that G-rk1 possesses potent anti-IAV effects in vitro and in vivo. We have also identified and characterized with a direct binding assay a novel ginseng-derived IAV HA1 inhibitor for the first time, which could present potential approaches to prevent and treat IAV infections.

ASSOCIATION OF CYCLING BETWEEN ANTI-TNFS VERSUS SWITCHING TO USTEKINUMAB WITH MEDICATION PERSISTENCE IN ANTI-TNF EXPERIENCED PATIENTS WITH CROHN'S DISEASE

Abstract BACKGROUND Anti-tumor necrosis factor inhibitors (anti-TNFs) are biologics commonly used for the treatment of Crohn’s disease (CD). Over time, patients may require adjustment to anti-TNF therapy, including cycling to a different anti-TNF or switching to a biologic with an alternate mechanism of action. Choice of a treatment strategy could be key to managing symptoms on a sustained basis. This study aimed to compare real-world persistence among patients with CD who cycled to another anti-TNF agent or switched to ustekinumab. METHODS Adults with CD treated with an anti-TNF, whose first switching to ustekinumab or cycling to a new anti-TNF (index date) occurred between 09/23/2016 and 08/01/2019 were selected from the IBM® MarketScan® Commercial Database. Patients had ≥12 months of continuous insurance eligibility before the initiation of the first anti-TNF, discontinued the first anti-TNF within 12 months before the index date (baseline), and had no other immune disorders during baseline. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence on index biologic (ustekinumab or a new anti-TNF) was defined as absence of therapy exposure gaps >120 days (ustekinumab, infliximab) or >60 days (adalimumab, certolizumab) between days of supply. Composite endpoints were persistence while on monotherapy (no immunomodulators/non-index biologics), and persistence and being corticosteroid-free (no corticosteroids with ≥14 days of supply after day 90 post-index). Weighted Kaplan-Meier and Cox models were used to assess outcomes at 12 months post-index. RESULTS The weighted sample included 325 patients in the ustekinumab cohort and 328 in the cycling cohort (Fig. 1). At 12 months post-index, 76.6% versus 67.5% persisted on the index biologic in the ustekinumab versus the cycling cohort (Fig. 2a); the rate of persistence was 47% higher in the ustekinumab cohort (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.08-2.01; p-value 0.0158). Moreover, 61.6% versus 44.1% persisted on the index biologic while on monotherapy, respectively (Fig. 2b); the rate of persistence while on monotherapy was 68% higher in the ustekinumab cohort (HR: 1.68; 95% CI: 1.33-2.13; p-value <0.001). Finally, 54.8% vs 50.2% were persistent and corticosteroid-free, respectively (Fig. 2c); the rate of being persistent and corticosteroid free numerically trended 9% higher in the ustekinumab cohort but statistical significance was not reached (HR: 1.09; 95% CI: 0.87-1.38; p-value 0.4527). CONCLUSIONS After discontinuation of the first anti-TNF, persistence on therapy was better among patients with CD who switched to ustekinumab compared to those who cycled to a new anti-TNF. These findings may inform treatment strategies for patients on the first anti-TNF agent who require treatment adjustment.

Targeting Leishmania donovani sterol methyltransferase for leads using pharmacophore modeling and computational molecular mechanics studies

The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between −7 and −11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane permeability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.

Study of the Oxolin antiviral drug effect for the improvement of potato seed material during in vitro cultivation

The article presents an analysis of the potato breeding problems in Russia which are associated with the low phytosanitary state of potato seed material infected with viral and bacterial diseases, as a result, it is necessary to carry out its improvement and the use of Russian varieties. Experiments were conducted in the laboratory of plant microclonal propagation according to the methodological recommendations for improvement and accelerated propagation of seed potatoes. The results of research on refining the technology of seed potato improvement by adding the Oxolin antiviral drug to the standard nutrient medium MS; its optimal concentrations for obtaining the largest number of uninfected plants of the studied varieties were identified. For potato varieties Liga, Hussar, and Real, the optimal concentration was 20 mg/l of Oxolin, while in the varieties Aurora, Real, and Sirenevy tuman, the concentration was 30 mg/l. Therefore, it is necessary to search for antiviral drugs with an alternative mechanism of action which remains very relevant and practically significant. The research results obtained in this work can be applied both to optimize the cultivation regime of potato microclones in vitro and to enhance the productive process of the uninfected microplants.

Advances in Breast Cancer Drug Discovery: A Review of Therapeutic Strategies and Studies Involving Photosensitizers, Caged Xanthones and Thiosemicarbazones Derivatives

Cancer is one of the major causes of death worldwide, and breast cancer is the most prevalent and deadly type among women. Despite the side effects and the phenomena of chemoresistance associated with the drugs involved, chemotherapy remains the main therapeutic strategy to combat and control breast cancer. Therefore, several new classes of compounds against breast cancer have been explored, in an effort to identify new drug candidates with alternative mechanisms of action. The principal results of such exploration, focusing on caged xanthones, thiosemicarbazones and photosensitizers, are presented in this review, along with the main aspects of the drug discovery process against breast cancer. More specifically, the design, structure-activity relationship investigations and anti-breast cancer properties of these three classes are described and discussed in this work.

Discovery and development of botanical natural products and their analogues as therapeutics for ovarian cancer.

Covering: 2015 through the end of July 2022Ovarian cancer is one of the most common cancers affecting the female reproductive organs and has the highest mortality rate among gynecological cancers. Although botanical drugs and their derivatives, namely members of the taxane and camptothecin families, represent significant therapeutics currently available for the treatment of ovarian cancer, new drugs that have alternative mechanisms of action are still needed to combat the disease. For this reason, many efforts to identify additional novel compounds from botanical sources, along with the further development of existing therapeutics, have continued to appear in the literature. This review is designed to serve as a comprehensive look at both the currently available small-molecule therapeutic options and the recently reported botanically-derived natural products currently being studied and developed as potential future therapeutics that could one day be used against ovarian cancer. Specifically, key properties, structural features, and biological data are highlighted that are important for the successful development of potential agents. Recently reported examples are specifically discussed in the context of "drug discovery attributes," including the presence of structure-activity relationship, mechanism of action, toxicity, and pharmacokinetic studies, to help indicate the potential for future development and to highlight where these compounds currently exist in the development process. The lessons learned from both the successful development of the taxanes and camptothecins, as well as the strategies currently being employed for new drug development, are expected to ultimately help guide the future development of botanical natural products for ovarian cancer.

A novel estrogen receptor 1-sphingomyelin phosphodiesterase acid like 3B pathway mediates rituximab response in myositis patients.

The B cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B-cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. Here we have: a) comprehensively investigated concurrent mRNA and microRNA expression in muscle biopsies taken at baseline and 16 weeks post treatment in ten patients who were part of the rituximab in myositis (RIM) trial; and b) investigated the beneficial effect of rituximab on myositis muscle cells. Our analyses identified an increased number of changes in gene expression in biopsies from patients who had a clinical response to rituximab (n = 5) compared with non-responders (n = 5). The two groups had completely different changes in microRNA and mRNA expression following rituximab therapy, with the exception of one mRNA, BHMT2. Networks of mRNA and microRNA with opposite direction of expression changes highlighted ESR1 as upregulated in responders. We confirmed ESR1 upregulation upon rituximab treatment of immortalized myotubes and primary human dermatomyositis muscle cells in vitro, demonstrating a direct effect of rituximab on muscle cells. Notably, despite showing a response to rituximab, human dermatomyositis primary muscle cells did not express the rituximab target, CD20. However, these cells expressed a possible alternative target of rituximab, sphingomyelinase-like phosphodiesterase 3 b (SMPDL3B). In addition to B cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells.

Evaluation of the phytotoxic and antifungal activity of C17 -sesquiterpenoids as potential biopesticides.

BACKGROUNDNatural products are a promising source for the development of new pesticides with alternative mechanisms of action. In this study, we evaluated the phytotoxic and antifungal activity of a novel family of natural C17‐sesquiterpenoids and performed a study of the effect caused by the elimination of the α‐methylene‐γ‐butyrolactone system and its importance to their biological activity.RESULTSMany tested compounds exhibited a strong phytotoxic activity. Lappalone and pertyolide B were the most potent molecules from the tested group. Lappalone displayed a strong inhibition profile against selected weed species, reaching a half‐maximal inhibitory concentration (IC50) value of 5.0 μm against Echinochloa crus‐galli L. shoot and 5.7 μm against the germination rate of Amaranthus viridis L., as well as a good stimulation of the germination of Phelipanche ramosa L. Pertyolide B demonstrated excellent inhibition against Amaranthus viridis L. (IC50: 56.7, 70.3 and 24.0 μm against the root and shoot growth, and germination rate, respectively) and Allium cepa L. (representative of the Liliaceae family, with IC50 values of 25.3 and 64.4 μm against root and shoot growth). Regarding the antifungal activity, pertyolide B presented significant activity against Colletotrichum fragareae and Fusarium oxysporum with a minimum inhibitory concentration of 6.6 μg μL−1.CONCLUSIONThe bioassays revealed that frequently the presence of the α‐methylene‐γ‐butyrolactone system is not essential for the bioactivities of sesquiterpene lactones, and suggest that C17‐sesquiterpenoids may function through a different mechanism of action not related to the widely assumed Michael addition. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Synergistic effect of Nisin with acetic and propionic acids inactivates Bacillus subtilis on meat and potato

B. subtilis can grow, survive, and cause spoilages of meat and potato samples. This situation represents both public health and economic concerns. The present work assessed the inhibitory effects of acetic and propionic acids in combination with Nisin (NS) in preventing meat and potato spoilage caused by B. subtilis. NS inactivated the contaminating microbe at 0.016 mg/ml, acetic and propionic acids at 0.13% v/v and 0.25% v/v respectively. NS (0.002 mg/ml) was combined with acetic acid at 0.065% v/v and propionic acid at 0.125% v/v to delay the rapid proliferation of the B. subtilis inoculated on meat and potato at 105 CFU/g. The samples were treated for 10 min and incubated for 10 day at 37 °C. Samples treated with purified water decreased the cell population to 4.21 log CFU/g after 10 min. While acetic, propionic, NS and 0.02N HCL show (3.68, 4.11, 4.05 and 4.15 log decreases). A further significant reduction (p < 0.05) happened after treatments with the combination of NS-acetic and NS-propionic acids (2.26 and 2.38 log CFU/g). DNA retardation analysis shows that neither NS nor acetic or propionic acid target DNA as alternative mechanism of action. At day 10, changes in the color of meat and potato samples treated with NS-organic acids were not significant (p < 0.05) when compared to the control. This is the first report showing the effectiveness of using NS, acetic and propionic acids concoction to control B. subtilis in meat and potato samples.

Improvement in clinical disease activity index when treatment selection is informed by the tumor necrosis factor-ɑ inhibitor molecular signature response classifier: analysis from the study to accelerate information of molecular signatures in rheumatoid arthritis

ABSTRACT Background A blood-based molecular signature response classifier (MSRC) predicts non-response to tumor necrosis factor-ɑ inhibitors (TNFi) in rheumatoid arthritis (RA). Research design and methods This is an interim analysis of data collected in the Study to Accelerate Information of Molecular Signatures (AIMS) in RA from patients who received the MSRC test between September 2020 and November 2021. Absolute changes in clinical disease activity index (CDAI) scores from baseline were evaluated at 12 weeks (n = 470) and 24 weeks (n = 274). Results Predicted TNFi non-responders who received a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) with an alternative mechanism of action (altMOA) experienced up to 1.8-fold greater improvements in CDAI scores than those treated with a TNFi (12 weeks: 12.2 vs 8.0; p-value = 0.083; 24 weeks: 14.2 vs 7.8 p-value = 0.009). In patients with a molecular signature of non-response to TNFi in high disease activity at baseline, this corresponded to 43.2% relative improvement in achieving a lower CDAI disease activity level when likely TNFi non-responders were treated with a non-TNFi therapy (38.9% vs 55.7%). Commensurate improvements in efficiency of spend are expected when TNFi are avoided in favor of altMOA. Conclusions RA treatment selection informed by MSRC test results improves clinical outcomes in real-world care and offers improvements in efficiency of healthcare spending.