Antiviral Therapy of COVID-19.

Since the beginning of the COVID-19 pandemic, the scientific community has focused on prophylactic vaccine development. In parallel, the experience of the pharmacotherapy of this disease has increased. Due to the declining protective capacity of vaccines against new strains, as well as increased knowledge about the structure and biology of the pathogen, control of the disease has shifted to the focus of antiviral drug development over the past year. Clinical data on safety and efficacy of antivirals acting at various stages of the virus life cycle has been published. In this review, we summarize mechanisms and clinical efficacy of antiviral therapy of COVID-19 with drugs based on plasma of convalescents, monoclonal antibodies, interferons, fusion inhibitors, nucleoside analogs, and protease inhibitors. The current status of the drugs described is also summarized in relation to the official clinical guidelines for the treatment of COVID-19. In addition, here we describe innovative drugs whose antiviral effect is provided by antisense oligonucleotides targeting the SARS-CoV-2 genome. Analysis of laboratory and clinical data suggests that current antivirals successfully combat broad spectra of emerging strains of SARS-CoV-2 providing reliable defense against COVID-19.

Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2.

Niclosamide, an oral anthelmintic drug, could inhibit SARS-CoV-2 virus replication through autophagy induction, but high cytotoxicity and poor oral bioavailability limited its application. Twenty-three niclosamide analogs were designed and synthesized, of which compound 21 was found to exhibit the best anti-SARS-CoV-2 efficacy (EC50 = 1.00 µM for 24 h), lower cytotoxicity (CC50 = 4.73 µM for 48 h), better pharmacokinetic, and it was also well tolerated in the sub-acute toxicity study in mice. To further improve the pharmacokinetics of 21, three prodrugs have been synthesized. The pharmacokinetics of 24 indicates its potential for further research (AUClast was 3-fold of compound 21). Western blot assay indicated that compound 21 could down-regulate SKP2 expression and increase BECN1 levels in Vero-E6 cells, indicating the antiviral mechanism of 21 was related to modulating the autophagy processes in host cells.

Molecular Insights into Resveratrol and Its Analogs as SARS-CoV-2 (COVID-19) Protease Inhibitors

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is plaguing the entire world. Amidst the pandemic, research and development efforts are fo-cused on the challenges associated with the SARS-CoV-2 structure. Material(s) and Method(s): Efficient computational methodologies are applied to screen the available FDA-approved drugs/datasets/libraries to identify potent molecules. In the present study, we have carried out ab initio quantum chemical studies, including relativistic effects followed by molecular docking with the SARS-CoV-2 protease target by employing a tailor-made library consisting of molecular analogs of Resveratrol, a natural bioflavonoid. Result(s): The derived docking results were validated with ab initio quantum computations that in-cluded both density functional level (DFT) and Moller-Plesset second order perturbation theories (MP2). We found to be that Resveratrol and its analogs (R8 and R17) bind to the SARS-CoV-2 protease target. In addition to this, the computed IR spectrum is found in agreement with the report-ed experimental spectra for Resveratrol complexes and thus validates the modeling and reliability of proposed geometries. The solvation energies in the aqueous phase obtained using enhanced aug-cc-pVTZ basis sets confirm enhancement of bioavailability for Resveratrol through piperine, a natural alkaloid. Conclusion(s): The potential of the natural bioflavonoid Resveratrol and its analogs to be investigated through in vivo and in vitro SARS-CoV-2 protease models is concluded. The study investigated the potential of natural polyphenols as promising anti-viral therapeutics.Copyright © 2021 Bentham Science Publishers.

Rna-Dependent Rna Polymerase (Rdrp) Inhibitor Drugs against Sars-Cov-2: A Molecular Docking Study

Objective: SARS-CoV-2 associated viral pandemic was first reported in Wuhan, China, in December 2019. Due to the rapid increase in its pathogenicity, SARS-CoV-2 was declared a global pandemic by WHO on March 11, 2020. For that reason, determining the most attractive viral protein targets became a must. One of the most important target proteins is SARS-COV-2 RNA-dependent RNA polymerase (RdRp) on which COVID-19 depends in its replication process. This study aimed to examine the possible interactions between RdRp and the most promising RdRp nucleoside inhibitors especially Purine nucleoside analogs, to detect the most important residues that commonly interact with RdRp's inhibitors and to investigate whether if there any mutations have been observed so far in these residues or not. Material(s) and Method(s): Molecular docking studies were carried out using AutoDock Vina between SARS-CoV-2 RdRp and drugs approved against different viral RdRps (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir, and Favipiravir) as well as physiological nucleotides (ATP and GTP). Based on the obtained results, a detailed surface-interaction analysis was also performed using Pymol and Discovery Studio Visualizer software for the models that exhibited the most suitable location and configuration in space. Result and Discussion: All the tested molecules were able to bind to SARS-CoV-2 RdRp successfully. Also, they all commonly interact with 9 different amino acids (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760, and Asp761), and 3 different Template-primer RNA nucleotides (U10, A11, and U20) causing inhibition of viral RdRp via non obligate RNA chain termination.Copyright © 2022 University of Ankara. All rights reserved.

Efficacy evaluation of quercetin and its analogues on the main protease enzyme of the COVID-19 using molecular docking studies

Introduction: COVID-19 is an acute respiratory infectious disease caused by the SARS-CoV-2 virus. There is an urgent need to discover antiviral drugs for better performance against new strains of coronaviruses (CoVs) due to the rapid spread of the disease despite scientific advances in vaccine development. This study aimed to evaluate the efficacy of quercetin and its analogues on the COVID-19 Mpro enzyme. Material & Methods: In this descriptive-analytical study, the three-dimensional structures of quercetin analogues (20 compounds), standard drugs (ritonavir and lopinavir), and the COVID-19 Mpro enzyme were obtained from PubChem and PDB databases for bioinformatics study, respectively. Molecular docking studies of the compounds on theMpro were performed using MOE-2014 software. Afterward, the physicochemical properties and biological activity of the compounds were predicted using Swiss ADME, PASS, and Swiss Target Prediction software. Findings: The findings of the present study showed that the most important bonds involved in drug-receptor binding are hydrogen, hydrophobic, and - interaction bonds. The best docking results were obtained for Baicalein, Genistein, Naringenin, and Quercetin compounds with strong binding energy (-12.83 to -13.54 kcal/mol), compared to ritonavir and lopinavir. These compounds have a greater tendency to bind to the catalytic amino acids His41 and Cys145 and other key amino acids of the active site of the COVID-19 Mpro enzyme. Discussion & Conclusion: Based on the results of bioinformatics studies, quercetin analogues had more effective inhibition than standard chemical drugs due to their suitable placement in the active site of the main protease enzyme of COVID-19 and can be good candidates for in vitro and in vivo studies.

Can plant-derived anti-HIV compounds be used in COVID-19 cases?

People living with HIV are more exposed to the adverse health effects of the worldwide COVID-19 pandemic. The pandemic's health and social repercussions may promote drug abuse and inadequate HIV management among this demographic. The coronavirus pandemic of 2019 (COVID-19) has caused unprecedented disruption worldwide in people's lives and health care. When the COVID-19 epidemic was identified, people with HIV faced significant obstacles and hurdles to achieving optimal care results. The viral spike protein (S-Protein) and the cognate host cell receptor angiotensin-converting enzyme 2 (ACE2) are both realistic and appropriate intervention targets. Calanolides A, Holy Basil, Kuwanon-L, and Patentiflorin have anti-HIV effects. Our computational biology study investigated that these compounds all had interaction binding scores related to S protein of coronavirus of -9.0 kcal /mol, -7.1 kcal /mol, -9.1 kcal /mol, and -10.3 kcal/mol/mol, respectively. A combination of plant-derived anti-HIV compounds like protease inhibitors and nucleoside analogs, which are commonly used to treat HIV infection, might be explored in clinical trials for the treatment of COVID-19.

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA.

The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC50 values in the range of 20-50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug.

The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types.

Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated pandemic of the corona virus disease (COVID-19) has led to enormous efforts in the development of medical countermeasures. Although innovative vaccines have scaled back the number of severe COVID cases, the emergence of the omicron variant (B.1.1.529) illustrates how vaccine development struggles to keep pace with viral evolution. On the other hand, while the recently approved antiviral drugs remdesivir, molnupiravir, and Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir and Paxlovid are orally available and none of these drugs are recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, and antiviral mechanisms are urgently needed to address issues in the current pandemic and in putative future outbreaks of newly emerging variants of concern. Recently, we and others have described the anti-infective potential and particularly the pronounced antiviral activity of artesunate and related compounds of the trioxane/sesquiterpene class. In particular, the trimeric derivative TF27 demonstrated strong anti-cytomegalovirus activity at nanomolar concentrations in vitro as well as in vivo efficacy after oral administration in therapeutic and even prophylactic treatment settings. Here, we extended this analysis by evaluating TF27 for its anti-SARS-CoV-2 potential. Our main findings are as follows: (i) compound TF27 exerted strong anti-SARS-CoV-2 activity in vitro (EC50 = 0.46 ± 0.20 µM), (ii) antiviral activity was clearly distinct from the induction of cytotoxicity, (iii) pretreatment with TF27 prevented virus replication in cultured cells, (iv) antiviral activity has likewise been demonstrated in Calu-3 human lung and Caco-2 human colon cells infected with wild-type, delta, or omicron SARS-CoV-2, respectively, and (v) analysis of TF27 combination treatments has revealed synergistic interaction with GC376, but antagonistic interaction with EIDD-1931. Combined, the data demonstrated the pronounced anti-SARS-CoV-2 activity of TF27 and thus highlight the potential of trioxane compounds for further pharmacologic development towards improved options for COVID-specific medication.

Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19.

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.

Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS-associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2-deoxy- d-glucose (2-DG) is an anticancer agent that is well-tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2. Because 2-DG inhibits glycolysis and N-glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2-DG with 2-fluoro-deoxy- d-glucose, a glycolysis inhibitor, and 2-deoxy-fluoro- d-mannose (2-DFM), a specific N-glycosylation inhibitor. At doses similar to those clinically achievable with 2-DG, the three drugs impair KSHV replication and virion production in iSLK.219 cells via downregulation of viral structural glycoprotein expression (K8.1 and gB), being 2-DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2-DFM, we found that d-mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of N-glycosylation is the main antiviral target using d-mannose competition experiments. Suppression of N-glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV-induced inhibition of the protein kinase R-like endoplasmic reticulum kinase branch, particularly activating transcription factor 4 and C/EBP homologous protein expression. Finally, we demonstrate that sugar analogs induce autophagy (a prosurvival mechanism) and, thus, inhibit viral replication playing a protective role against KSHV-induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of N-glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2-DG and the newly identified 2-DFM as antiviral drugs.

Long-term oral administration of Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. decoction and its aristolochic acid analogs do not cause renal toxicity in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. (AH) is widely used to treat influenza, COVID-19, allergic rhinitis, headache, toothache, rheumatoid arthritis, and peptic ulcer. However, its clinical use is controversial due to the concern of aristolochic acid nephropathy (AAN) caused by its component aristolochic acid analogs (AAs). AIM OF THE STUDY: The chronic toxicity of AH decoction and its main components AA IVa (AA-IVa) and aristolactam I (AL-I) was evaluated in mice. MATERIALS AND METHODS: AAs contents in AH were quantitated by liquid chromatography-mass spectrometry. A parallel design was employed to examine the potential chronic toxicity of AH decoction at doses equivalent to 0.5, 1.6, and 5.0 g/kg AH (approximately 10-100 times the clinical doses for humans) and its major AA components at doses equivalent to that in 5.0 g/kg AH to mice after consecutive daily oral administration for 12 and 24 weeks, and at 32 weeks after withdrawal for 8 weeks. RESULTS: AH crude herb contained 2.18 µg/g of AA-I, 48.49 µg/g of AA-IVa, and 14.0 µg/g of AL-I. AH decoction contained 5.45 µg/g of AA-IVa and 2.71 µg/g of AL-I. None of AA-II and AA-IIIa were detected in AH. After long-term administration of AH decoction and its major components AA-IVa and AL-I, mice showed no signs of illness or body weight changes. In addition, biochemical and pathohistological examinations showed that long-term administration of AH decoction and its major components AA-IVa and AL-I did not alter 1) serum levels of glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, creatinine, and urea nitrogen, 2) renal tissue mRNA expression of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, and 3) pathological morphology in the mouse liver, kidney, stomach, and bladder. CONCLUSIONS: AH has no obvious toxicity to mice and is relatively safe when it is used in the form of decoction. AA-IVa and AL-I, the two major AAs in AH, are not toxic to mice at the dose equivalent to that in the high dose of AH decoction. Considering the limited toxicological data on AH, we recommend that AH decoction medication should not overdose and the duration should not be too long.

Structural Insight into 2-Aryl-4-Quinoline Carboxylic Acid-Based Dihydroorotate Dehydrogenase (DHODH) and its Potential Anti-SARS-CoV-2 Activity Through Pharmacophore Modeling, Multidimensional QSAR, ADME, and Docking Studies

Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the biosynthesis of pyrimidine, which catalyzes the oxidation of dihydroorotate to orotate. Uridine monophosphate is biosynthesized by orotate. DHODH inhibitors have been shown to have antiviral activity against cytomegalovirus, Ebola, influenza, Epstein-Barr virus, and picornavirus. The anti-SARS-CoV-2 activity of DHODH inhibitors has also been investigated. DHODH inhibitors, including leflunomide and its metabolite teriflunomide, have been found to have anti-SARSCoV-2 activity. In relation to the importance of this enzyme (i.e., DHODH) in drug design, the present study aimed to develop statistically robust and interpretable 2D and 3D-quantitative structure-activity relationship (QSAR) models based on a dataset of 92 molecules of biologically active 2-aryl-4-quinoline carboxylic acid analogs, reported as DHODH inhibitors. The correlation coefficient (R2) values of the training set of the partial least squares (PLS) and all five Kernel-based PLS models for the respective fingerprints were found to be 0.7091, 0.8336 (linear), 0.7586 (radial), 0.8606 (dendritic), 0.6832 (desc), and 0.7670 (Molprint 2D), respectively (R2 ≈ 0.9). However, the external validation coefficient (Q2) values of the test set were found to be 0.7009, 0.7503 (linear), 0.7737 (radial), 0.8250 (dendritic), 0.6756 (desc), and 0.7533 (Molprint 2D), respectively (Q2 > 0.6). The developed 4-point pharmacophore model (ARRR_1), with one hydrogen bond acceptor and three aromatic rings, was found to be crucial in preserving the activity of 2-aryl-4-quinoline carboxylic acid analogs as DHODH inhibitors. Furthermore, the molecular docking of DHODH inhibitors against SARS-CoV-2 target proteins revealed the significant role of DHODH inhibitors. © 2023, Physical Chemistry Research. All Rights Reserved.

N-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents.

New N-containing xanthone analogs of α-mangostin were synthesized via one-pot Smiles rearrangement. Using cesium carbonate in the presence of 2-chloroacetamide and catalytic potassium iodide, α-mangostin (1) was subsequently transformed in three steps to provide ether 2, amide 3, and amine 4 in good yields at an optimum ratio of 1:3:3, respectively. The evaluation of the biological activities of α-mangostin and analogs 2-4 was described. Amine 4 showed promising cytotoxicity against the non-small-cell lung cancer H460 cell line fourfold more potent than that of cisplatin. Both compounds 3 and 4 possessed antitrypanosomal properties against Trypanosoma brucei rhodesiense at a potency threefold stronger than that of α-mangostin. Furthermore, ether 2 gave potent SARS-CoV-2 main protease inhibition by suppressing 3-chymotrypsinlike protease (3CLpro) activity approximately threefold better than that of 1. Fragment molecular orbital method (FMO-RIMP2/PCM) indicated the improved binding interaction of 2 in the 3CLpro active site regarding an additional ether moiety. Thus, the series of N-containing α-mangostin analogs prospectively enhance druglike properties based on isosteric replacement and would be further studied as potential biotically active chemical entries, particularly for anti-lung-cancer, antitrypanosomal, and anti-SARS-CoV-2 main protease applications.

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.

Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.

Synthesis of new 3-acetyl-1,3,4-oxadiazolines combined with pyrimidines as antileishmanial and antiviral agents.

A new series of 3-acetyl-1,3,4-oxadiazoline hybrid molecules was designed and synthesized using a condensation between acyclonucleosides and substituted phenylhydrazone. All intermediates and final products were screened against Leishmania donovani, a Protozoan parasite and against three viruses SARS-CoV-2, HCMV and VZV. While no significant activity was observed against the viruses, the intermediate with 6-azatymine as thymine and 5-azathymine-3-acetyl-1,3,4-oxadiazoline hybrid exhibited a significant antileishmanial activity. The later compound was the most promising, exhibiting an IC50 value at 8.98 µM on L. donovani intramacrophage amastigotes and a moderate selectivity index value at 2.4.

Comparative Assessment of the Inhibitory Potential of the Herbicide Glyphosate and Its Structural Analogs on RGD-Specific Integrins Using Enzyme-Linked Immunosorbent Assays.

Transmembrane glycoprotein integrins play crucial roles in biochemical processes, and by their inhibition or activation, different signal pathways can be disrupted, leading to abnormal physiological functions. We have previously demonstrated the inhibitory effect of glyphosate herbicide's active ingredient on cell adhesion and its αvß3 integrin antagonist effect. Therefore, it appeared particularly exciting to investigate inhibition of glyphosate and its metabolites on a wider range of Arg-Gly-Asp (RGD) binding integrins, namely αvß3, α5ß1 and αllbß3. Thus, the purpose of this study was to assess how extended the inhibitory effect observed for glyphosate on the integrin αvß3 is in terms of other RGD integrins and other structurally or metabolically related derivatives of glyphosate. Five different experimental setups using enzyme-linked immunosorbent assays were applied: (i) αvß3 binding to a synthetic polymer containing RGD; (ii) αvß3 binding to its extracellular matrix (ECM) protein, vitronectin; (iii) α5ß1 binding to the above polymer containing RGD; (iv) αllbß3 binding to its ECM protein, fibrinogen and (v) αvß3 binding to the SARS-CoV-2 spike protein receptor binding domain. Total inhibition of αvß3 binding to RGD was detected for glyphosate and its main metabolite, aminomethylphosphonic acid (AMPA), as well as for acetylglycine on α5ß1 binding to RGD.

Structural Insights Into Tautomeric Dynamics in Nucleic Acids and in Antiviral Nucleoside Analogs.

DNA (2'-deoxyribonucleic acid) and RNA (ribonucleic acid) play diverse functional roles in biology and disease. Despite being comprised primarily of only four cognate nucleobases, nucleic acids can adopt complex three-dimensional structures, and RNA in particular, can catalyze biochemical reactions to regulate a wide variety of biological processes. Such chemical versatility is due in part to the phenomenon of nucleobase tautomerism, whereby the bases can adopt multiple, yet distinct isomeric forms, known as tautomers. For nucleobases, tautomers refer to structural isomers that differ from one another by the position of protons. By altering the position of protons on nucleobases, many of which play critical roles for hydrogen bonding and base pairing interactions, tautomerism has profound effects on the biochemical processes involving nucleic acids. For example, the transient formation of minor tautomers during replication could generate spontaneous mutations. These mutations could arise from the stabilization of mismatches, in the active site of polymerases, in conformations involving minor tautomers that are indistinguishable from canonical base pairs. In this review, we discuss the evidence for tautomerism in DNA, and its consequences to the fidelity of DNA replication. Also reviewed are RNA systems, such as the riboswitches and self-cleaving ribozymes, in which tautomerism plays a functional role in ligand recognition and catalysis, respectively. We also discuss tautomeric nucleoside analogs that are efficacious as antiviral drug candidates such as molnupiravir for coronaviruses and KP1212 for HIV. The antiviral efficacy of these analogs is due, in part, to their ability to exist in multiple tautomeric forms and induce mutations in the replicating viral genomes. From a technical standpoint, minor tautomers of nucleobases are challenging to identify directly because they are rare and interconvert on a fast, millisecond to nanosecond, time scale. Nevertheless, many approaches including biochemical, structural, computational and spectroscopic methods have been developed to study tautomeric dynamics in RNA and DNA systems, and in antiviral nucleoside analogs. An overview of these methods and their applications is included here.

Synthesis and Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways.

Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiols A-C, reported previously from Machaerium Pers., have displayed potent activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and E. faecalis (VRE). In order to enrich the pipeline of natural product-derived antimicrobial compounds, a series of novel machaeridiol-based analogs (1-17) were prepared by coupling stemofuran, pinosylvin, and resveratrol legends with monoterpene units R-(-)-α-phellandrene, (-)-p-mentha-2,8-diene-1-ol, and geraniol, and their inhibitory activities were profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activities with MIC values of 2.5 µg/mL and 1.25 µg/mL against MRSA, respectively, and 2.50 µg/mL against VRE, while geranyl analog 14 was found to be moderately active (MIC 5 µg/mL). The reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had the same antibacterial potency (MIC 1.25 µg/mL and 2.50 µg/mL) as its parent, 5. Furthermore, a combination study between seco-HHDBP 17 and HHDBP machaeriol C displayed a synergistic effect with a fractional inhibitory concentrations (FIC) value of 0.5 against MRSA, showing a four-fold decrease in the MIC values of both 17 and machaeriol C, while no such effect was observed between vancomycin and 17. Compounds 11 and 17 were further tested in vivo against nosocomial MRSA at a single intranasal dose of 30 mg/kg in a murine model, and both compounds were not efficacious under these conditions. Finally, compounds 1-17 were profiled against a panel of luciferase genes that assessed the activity of complex cancer-related signaling pathways (i.e., transcription factors) using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl-substituted analog 14 exhibited strong inhibition against several signaling pathways, notably Smad, Myc, and Notch, with IC50 values of 2.17 µM, 1.86 µM, and 2.15 µM, respectively. In contrast, the anti-MRSA actives 5 and 17 were found to be inactive (IC50 > 20 µM) across the panel of these cancer-signaling pathways.

CML-466 Asciminib Provides Durable Molecular Responses in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With the T315I Mutation: Updated Efficacy and Safety Data From a Phase I Trial

CONTEXT: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib-a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket-demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). OBJECTIVE: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. DESIGN: Patients with T315I-mutated CML-CP and treated with >=1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). RESULTS: 48 patients were included;25 patients (52.1%) received >=3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients;34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for >=96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS <=1% by week 96. The safety/tolerability profile of asciminib remained favorable after =9 months of added exposure (median duration of exposure, 2.08 years;range, 0.04-4.13 years). The most common (>=10%) grade >=3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%);none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. CONCLUSIONS: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP-a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.

Psychotropic drugs interaction with the lipid nanoparticle of COVID-19 mRNA therapeutics.

The messenger RNA (mRNA) vaccines for COVID-19, Pfizer-BioNTech and Moderna, were authorized in the US on an emergency basis in December of 2020. The rapid distribution of these therapeutics around the country and the world led to millions of people being vaccinated in a short time span, an action that decreased hospitalization and death but also heightened the concerns about adverse effects and drug-vaccine interactions. The COVID-19 mRNA vaccines are of particular interest as they form the vanguard of a range of other mRNA therapeutics that are currently in the development pipeline, focusing both on infectious diseases as well as oncological applications. The Vaccine Adverse Event Reporting System (VAERS) has gained additional attention during the COVID-19 pandemic, specifically regarding the rollout of mRNA therapeutics. However, for VAERS, absence of a reporting platform for drug-vaccine interactions left these events poorly defined. For example, chemotherapy, anticonvulsants, and antimalarials were documented to interfere with the mRNA vaccines, but much less is known about the other drugs that could interact with these therapeutics, causing adverse events or decreased efficacy. In addition, SARS-CoV-2 exploitation of host cytochrome P450 enzymes, reported in COVID-19 critical illness, highlights viral interference with drug metabolism. For example, patients with severe psychiatric illness (SPI) in treatment with clozapine often displayed elevated drug levels, emphasizing drug-vaccine interaction.