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1.
J Manag Care Spec Pharm ; 30(8): 817-824, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39088337

ABSTRACT

BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.


Subject(s)
Anti-HIV Agents , HIV Infections , Pyridones , Humans , HIV Infections/drug therapy , HIV Infections/economics , Retrospective Studies , Female , Male , Adult , Middle Aged , Pyridones/economics , Pyridones/therapeutic use , Anti-HIV Agents/economics , Anti-HIV Agents/therapeutic use , Heterocyclic Compounds, 3-Ring/economics , Heterocyclic Compounds, 3-Ring/therapeutic use , Tenofovir/therapeutic use , Tenofovir/economics , Patient Acceptance of Health Care/statistics & numerical data , Health Care Costs/statistics & numerical data , Drug Combinations , Oxazines/therapeutic use , Oxazines/economics , Emtricitabine/therapeutic use , Emtricitabine/economics , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/economics , Piperazines/economics , Piperazines/therapeutic use , Lamivudine/economics , Lamivudine/therapeutic use , HIV Integrase Inhibitors/economics , HIV Integrase Inhibitors/therapeutic use , Health Resources/economics , Health Resources/statistics & numerical data , Drug Substitution/economics , Amides , Cyclopropanes , Dideoxyadenosine/analogs & derivatives
2.
AIDS Res Ther ; 21(1): 45, 2024 07 10.
Article in English | MEDLINE | ID: mdl-38987825

ABSTRACT

BACKGROUND: The rapid start of antiretroviral therapy (RSA) model initiates antiretroviral therapy (ART) as soon as possible after a new or preliminary diagnosis of HIV, in advance of HIV-1 RNA and other baseline laboratory testing. This observational study aims to determine if RSA with a single tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) is an effective regimen for achieving viral suppression and accepted by patients at the time of diagnosis. METHODS: Adults newly or preliminarily diagnosed with HIV were enrolled from October 2018 through September 2021. Real world advantage, measured in days between clinical milestones and time to virologic suppression, associated with B/F/TAF RSA was compared to historical controls. RESULTS: All Study RSA participants (n = 45) accepted treatment at their first visit and 43(95.6%) achieved virologic suppression by week 48. Study RSA participants had a significantly shorter time (median 32 days) from diagnosis to ART initiation and virologic suppression, in comparison to historical controls (median 181 days) (n = 42). Qualitative feedback from study RSA participants showed high acceptance positive response to RSA. CONCLUSIONS: RSA is feasible and well accepted by patients in a real-world community-based clinic setting. Promoting RSA in community-based clinics is an important tool in ending the HIV epidemic.


Subject(s)
Anti-HIV Agents , Emtricitabine , HIV Infections , Tenofovir , Humans , HIV Infections/drug therapy , Pilot Projects , Male , Female , Adult , Tenofovir/therapeutic use , Tenofovir/administration & dosage , Tenofovir/analogs & derivatives , Middle Aged , Anti-HIV Agents/therapeutic use , Emtricitabine/therapeutic use , Emtricitabine/administration & dosage , Alanine/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/administration & dosage , HIV-1/drug effects , Piperazines/therapeutic use , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Viral Load/drug effects , Amides/therapeutic use , RNA, Viral/blood , Pyridones
3.
Int J Mol Sci ; 25(13)2024 Jun 26.
Article in English | MEDLINE | ID: mdl-39000109

ABSTRACT

Surface modification of drug-loaded particles with polyethylene glycol (PEG) chains is a powerful tool that promotes better transport of therapeutic agents, provides stability, and avoids their detection by the immune system. In this study, we used a new approach to synthesize a biodegradable poly(ester amide) (PEA) and PEGylating surfactant. These were employed to fabricate micro/nanoparticles with a core-shell structure. Nanoparticle (NP)-protein interactions and self-assembling were subsequently studied by synchrotron radiation-based FTIR microspectroscopy (SR-FTIRM) and transmission electron microscopy (TEM) techniques. The core-shell structure was identified using IR absorption bands of characteristic chemical groups. Specifically, the stretching absorption band of the secondary amino group (3300 cm-1) allowed us to identify the poly(ester amide) core, while the band at 1105 cm-1 (C-O-C vibration) was useful to demonstrate the shell structure based on PEG chains. By integration of absorption bands, a 2D intensity map of the particle was built to show a core-shell structure, which was further supported by TEM images.


Subject(s)
Nanoparticles , Polyesters , Polyethylene Glycols , Synchrotrons , Polyethylene Glycols/chemistry , Spectroscopy, Fourier Transform Infrared/methods , Nanoparticles/chemistry , Polyesters/chemistry , Microscopy, Electron, Transmission/methods , Amides/chemistry
5.
Biochemistry ; 63(14): 1774-1782, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-38958242

ABSTRACT

ProTides are nucleotide analogues used for the treatment of specific viral infections. These compounds consist of a masked nucleotide that undergoes in vivo enzymatic and spontaneous chemical transformations to generate a free mononucleotide that is ultimately transformed to the pharmaceutically active triphosphorylated drug. The three FDA approved ProTides are composed of a phosphoramidate (P-N) core coupled with a nucleoside analogue, phenol, and an l-alanyl carboxylate ester. The previously proposed mechanism of activation postulates the existence of an unstable 5-membered mixed anhydride cyclic intermediate formed from the direct attack of the carboxylate group of the l-alanyl moiety with expulsion of phenol. The mixed anhydride cyclic intermediate is further postulated to undergo spontaneous hydrolysis to form a linear l-alanyl phosphoramidate product. In the proposed mechanism of activation, the 5-membered mixed anhydride intermediate has been detected previously using mass spectrometry, but the specific site of nucleophilic attack by water (P-O versus C-O) has not been determined. To further interrogate the mechanism for hydrolysis of the putative 5-membered cyclic intermediate formed during ProTide activation, the reaction was conducted in 18O-labeled water using a ProTide analogue that could be activated by carboxypeptidase Y. Mass spectrometry and 31P NMR spectroscopy were used to demonstrate that the hydrolysis of the mixed anhydride 5-membered intermediate occurs with exclusive attack at the phosphorus center.


Subject(s)
Phosphoric Acids , Hydrolysis , Phosphoric Acids/chemistry , Phosphoric Acids/metabolism , Amides/chemistry , Amides/metabolism , Stereoisomerism , Oxygen Isotopes/chemistry , Anhydrides/chemistry , Magnetic Resonance Spectroscopy/methods , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Water/chemistry , ProTides
6.
Sci Rep ; 14(1): 16785, 2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39039129

ABSTRACT

A lack of adherence to long-term antiretroviral therapy may impact viral suppression. The current study examined the relationship between medication adherence and clinical outcomes in people with human immunodeficiency virus infection (PWH) receiving bictegravir, emtricitabine, and tenofovir alafenamide fumarate (B/F/TAF). A retrospective cohort study using two Japanese claims databases was conducted. Adherence was measured by the proportion of days covered (PDC). Patients were grouped into 3 PDC category and persistence was estimated by Kaplan-Meier method. Cox regression analysis was performed to investigate whether the PDC was associated with treatment discontinuation. Among 952 patients, 820 (86.1%), 95 (10.0%), and 37 (3.9%) patients were grouped into the PDC ≥ 90%, 80- < 90%, and < 80% groups, respectively. Across all PDC groups, more than 90% of patients who received B/F/TAF were receiving treatment at 1 year. There was no significant difference in the risk of discontinuation between the lower PDC groups (80- < 90% and < 80%) and the PDC ≥ 90% group (0.400 [0.096, 1.661]; 2.244 [0.663, 7.594], hazard ratio [95% confidence interval], respectively). A drug resistance test was implemented for 15 patients, none of whom discontinued B/F/TAF after the test. The results suggest that events that could cause discontinuation, such as virologic failure, were not associated with PDC.


Subject(s)
Alanine , Anti-HIV Agents , Emtricitabine , HIV Infections , Medication Adherence , Pyridones , Tenofovir , Humans , Tenofovir/therapeutic use , Tenofovir/analogs & derivatives , Male , Female , HIV Infections/drug therapy , HIV Infections/virology , Emtricitabine/therapeutic use , Japan , Middle Aged , Retrospective Studies , Adult , Anti-HIV Agents/therapeutic use , Alanine/therapeutic use , Alanine/analogs & derivatives , Pyridones/therapeutic use , Piperazines/therapeutic use , Treatment Outcome , Amides/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Adenine/analogs & derivatives , Adenine/therapeutic use , Databases, Factual , Drug Combinations
7.
Viruses ; 16(7)2024 Jul 09.
Article in English | MEDLINE | ID: mdl-39066263

ABSTRACT

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013-2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.


Subject(s)
Amides , Antiviral Agents , Disease Models, Animal , Ebolavirus , Hemorrhagic Fever, Ebola , Mice, Inbred BALB C , Pyrazines , Animals , Amides/therapeutic use , Amides/administration & dosage , Amides/pharmacology , Guinea Pigs , Pyrazines/administration & dosage , Pyrazines/therapeutic use , Hemorrhagic Fever, Ebola/drug therapy , Mice , Ebolavirus/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Female , Drug Administration Routes , Drug Administration Schedule
8.
Inorg Chem ; 63(30): 13893-13902, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39011904

ABSTRACT

Two new p-cresol-2,6-bis(amide-tether-dpa4-X) ligands (HL4-X, X = MeO and Cl) and their dicopper complexes [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L4-MeO)]Y (Y = PF6 1a, OAc 1b) and [Cu2(µ-1,3-OAc)2(L4-Cl)]Y (Y = ClO4 2a, OAc 2b) were synthesized. The electronic and hydrophobic effects of the MeO and Cl groups were examined compared with nonsubstituted complex [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L)]+ (3). The electronic effects were found in crystal structures, spectroscopic characterization, and redox potentials of these complexes. 1b and 2b were reduced to Cu(I)Cu(I) with sodium ascorbate and reductively activated O2 to produce H2O2 and HO•. The H2O2 release and HO• generation are promoted by the electronic effects. The hydrophobic effects increased the lipophilicity of 1b and 2b. Cellular ROS generation of 1b, 2b, and 3 was visualized by DCFH-DA. To examine the intracellular behavior, boron dipyrromethene (Bodipy)-modified complexes 4B and 5B corresponding to 1b and 2b were synthesized. These support that 1b and 2b are localized at the ER and Golgi apparatus. The cytotoxicity of 1b and 2b against various cell lines was examined by MTT assay. 1b and 2b were 7- and 41-fold more cytotoxic than 3. 1b generated ROS selectively in cancer cell but 2b nonselectively in cancer and normal cells, causing cancer- and normal-cell-selective cytotoxicity, respectively.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Copper , Hydrophobic and Hydrophilic Interactions , Reactive Oxygen Species , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Reactive Oxygen Species/metabolism , Copper/chemistry , Copper/pharmacology , Drug Screening Assays, Antitumor , Molecular Structure , Cresols/chemistry , Cresols/pharmacology , Cresols/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Cell Proliferation/drug effects , Electrons , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis
9.
Bioorg Med Chem Lett ; 110: 129859, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-38955244

ABSTRACT

In this study, we report on the ability of DMTMM PF6 to improve the amidation reaction. The on-DNA amidation reaction using DMTMM PF6 demonstrates higher conversion rates than those using HATU or DMTMM Cl, particularly with challenging sterically hindered amines and carboxylic acids. The developed method enables the expansion of available building blocks and the efficient synthesis of high-purity DNA-encoded libraries.


Subject(s)
Amides , DNA , Amides/chemistry , Amides/chemical synthesis , DNA/chemistry , Molecular Structure , Small Molecule Libraries/chemistry , Small Molecule Libraries/chemical synthesis , Gene Library
10.
Sci Rep ; 14(1): 17097, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39048611

ABSTRACT

GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient's iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy.


Subject(s)
Cell Differentiation , GTP-Binding Protein alpha Subunits, Gi-Go , Induced Pluripotent Stem Cells , Neurons , Signal Transduction , rho GTP-Binding Proteins , Humans , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Neurons/metabolism , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/cytology , rho GTP-Binding Proteins/metabolism , rho GTP-Binding Proteins/genetics , Mice , Animals , rho-Associated Kinases/metabolism , Organoids/metabolism , Amides/pharmacology , Pyridines
11.
Sci Rep ; 14(1): 16290, 2024 07 15.
Article in English | MEDLINE | ID: mdl-39009738

ABSTRACT

Bictegravir, a key second-generation integrase strand transfer inhibitor in the treatment of HIV, is subject to active efflux transport mediated by ABCB1 (P-glycoprotein). Several coding variants of ABCB1 have been described and associated with variable effects on substrate drugs pharmacokinetics. Here, we investigated the effect of the four most common coding ABCB1 single nucleotide polymorphisms (i.e., c.1199G > A, c.1236C > T, c.2677G > T and c.3435C > T) on the intracellular accumulation of bictegravir. Using a previously validated HEK293 recombinant cell line model, we found decreased bictegravir intracellular concentrations in cell lines overexpressing ABCB1 as compared to control cell lines, in line with the known role of ABCB1 in bictegravir transport. However, we were unable to demonstrate any significant difference in bictegravir intracellular accumulation when comparing HEK293 cells overexpressing the wild type (1236C-2677G-3435C, 1199G) or the variant (1236C-2677G-3435T, 1236T-2677T-3435T or 1199A) proteins. These findings suggest that the ABCB1 c.1199G > A and c.1236C > T-c.2677G > T-c.3435C > T variants have no or at least limited impact on the active transport of bictegravir by ABCB1.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B , Piperazines , Polymorphism, Single Nucleotide , Humans , HEK293 Cells , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Piperazines/metabolism , Heterocyclic Compounds, 3-Ring/metabolism , Amides/metabolism , Pyridones/metabolism , Heterocyclic Compounds, 4 or More Rings/metabolism
12.
J Med Chem ; 67(14): 12261-12313, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-38959455

ABSTRACT

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against ß-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.


Subject(s)
Antiviral Agents , Casein Kinase II , Pyrimidines , Triazoles , Virus Replication , Triazoles/pharmacology , Triazoles/chemistry , Triazoles/chemical synthesis , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Animals , Humans , Virus Replication/drug effects , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Pyrazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Structure-Activity Relationship , Mice , Rats , SARS-CoV-2/drug effects , Drug Discovery , Male
13.
J Med Chem ; 67(14): 11989-12011, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-38959216

ABSTRACT

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.


Subject(s)
Inflammatory Bowel Diseases , Receptors, Purinergic P2 , Thiophenes , Animals , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/therapeutic use , Humans , Mice , Inflammatory Bowel Diseases/drug therapy , Receptors, Purinergic P2/metabolism , Structure-Activity Relationship , Purinergic P2 Receptor Antagonists/pharmacology , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/therapeutic use , Male , Drug Discovery , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Amides/therapeutic use , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Colitis/drug therapy
14.
Bioorg Chem ; 150: 107580, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38959646

ABSTRACT

α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a-n were investigated. Galbanic acid and compounds 3a-n showed excellent anti-α-glucosidase activity with IC50 values ranging from 0.3 ± 0.3 µM to 416.0 ± 0.2 µM in comparison to positive control acarbose with IC50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with Ki = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents.


Subject(s)
Amides , Glycoside Hydrolase Inhibitors , Molecular Docking Simulation , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/chemical synthesis , alpha-Glucosidases/metabolism , Humans , Structure-Activity Relationship , Molecular Structure , Amides/chemistry , Amides/pharmacology , Amides/chemical synthesis , Dose-Response Relationship, Drug , Saccharomyces cerevisiae/enzymology
15.
Int J Nanomedicine ; 19: 7399-7414, 2024.
Article in English | MEDLINE | ID: mdl-39071500

ABSTRACT

Background: Influenza A (H1N1) virus is a highly contagious respiratory disease that causes severe illness and death. Vaccines and antiviral drugs are limited by viral variation and drug resistance, so developing efficient integrated theranostic options appears significant in anti-influenza virus infection. Methods: In this study, we designed and fabricated covalent organic framework (COF) based theranostic platforms (T705@DATA-COF-Pro), which was composed of an RNA polymerase inhibitor (favipiravir, T705), the carboxyl-enriched COF (DATA-COF) nano-carrier and Cy3-labeled single DNA (ssDNA) probe. Results: The multi-porosity COF core provided an excellent micro-environment and smooth delivery for T705. The ssDNA probe coating bound to the nucleic acids of H1N1 selectively, thus controlling drug release and allowing fluorescence imaging. The combination of COF and probe triggered the synergism, promoting drug further therapeutic outcomes. With the aid of T705@DATA-COF-Pro platforms, the H1N1-infected mouse models lightly achieved diagnosis and significantly prolonged survival. Conclusion: This research underscores the distinctive benefits and immense potential of COF materials in nano-preparations for virus infection, offering novel avenues for the detection and treatment of H1N1 virus infection.


Subject(s)
Antiviral Agents , Influenza A Virus, H1N1 Subtype , Metal-Organic Frameworks , Orthomyxoviridae Infections , Theranostic Nanomedicine , Influenza A Virus, H1N1 Subtype/drug effects , Animals , Theranostic Nanomedicine/methods , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Mice , Orthomyxoviridae Infections/drug therapy , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Humans , Amides/chemistry , Amides/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Influenza, Human/drug therapy , Mice, Inbred BALB C , Madin Darby Canine Kidney Cells , Drug Carriers/chemistry , Dogs , Drug Liberation
16.
Med Gas Res ; 14(3): 102-107, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-39073337

ABSTRACT

This study aimed to compare the effects of intrathecal dexmedetomidine, fentanyl and magnesium sulfate added to ropivacaine on the onset and duration of sensory and motor blocks in lower abdominal surgery. This double-blind randomized clinical trial included 90 patients scheduled for lower abdominal surgery at Vali-Asr Hospital in Arak, Iran. The enrolled patients were randomly divided into three equal groups and then underwent spinal anesthesia. The first group received 10 µg of dexmedetomidine, the second group received 50 µg of fentanyl, and the third group received 200 mg of 20% magnesium sulfate intrathecally in addition to 15 mg of 0.5% ropivacaine. In the dexmedetomidine group, the mean arterial blood pressure was lower than the other two groups (P = 0.001). Moreover, the time to onset of sensory block (P = 0.001) and the mean duration of sensory block (P = 0.001) were shorter and longer, respectively, in the dexmedetomidine group than in the other two groups. In the dexmedetomidine group, the mean time to onset of motor block (P = 0.001) and the mean duration of motor block (P = 0.001) were lower and higher than in the other two groups, respectively. There was no significant difference in visual analog scale score, heart rate, administered opioid, and drug side effects among the three groups. Dexmedetomidine caused early sensory and motor blocks while prolonging the duration of sensory and motor blocks compared with the other two groups. In addition, dexmedetomidine reduced mean arterial blood pressure in patients. Based on the findings of this study, it is recommended that dexmedetomidine can be used in order to enhance the quality of sensory and motor block in patients.


Subject(s)
Dexmedetomidine , Fentanyl , Magnesium Sulfate , Ropivacaine , Humans , Dexmedetomidine/administration & dosage , Dexmedetomidine/pharmacology , Male , Magnesium Sulfate/pharmacology , Magnesium Sulfate/administration & dosage , Female , Ropivacaine/pharmacology , Ropivacaine/administration & dosage , Fentanyl/administration & dosage , Fentanyl/pharmacology , Fentanyl/adverse effects , Middle Aged , Adult , Double-Blind Method , Abdomen/surgery , Amides/administration & dosage , Amides/pharmacology
17.
Sci Rep ; 14(1): 17697, 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39085399

ABSTRACT

In this study, Density-functional theory/Time-dependent density-functional theory (DFT/TDDFT) and Molecular docking method was used to investigate the effect of methyl acetate, tetrahydrofuran and cyanobenzylidene substituents on the electronic structure and antiviral activity of favipiravir for treating COVID-19. The DFT and TDDFT computations were employed using the Gaussian 09 software package. The values were calculated using the 6-311++G(d, p) basis set and the hybrid B3LYP functional method. Autodock vina software was used for simulations to better predictions and to validate the modified compounds' binding affinities and poses. Results of the study indicate that compounds 1 to 6 all displayed a planar structure, where the pyrazine ring, carboxamide, hydroxyl groups, and other substituents are all situated within the same plane. In addition, the energy gaps (Egap) of these six compounds (Cpd 1, 2, 3, 4, 5, and 6) were compared. The significant dipole moment and binding affinity achieved implies a particular orientation for binding within the target protein, signaling the anticipated strength of the binding interaction. In all six compounds, the electrophilic domain is situated in the vicinity of the amine functional group within the carboxamide compound, whereas the nucleophilic domain encompasses both the carbonyl and hydroxyl groups. The most negatively charged sites are susceptible to electrophilic interactions. In conclusion, compounds 5 and 6 exhibit a high binding affinity of the target protein, while compound 6 has a high energy gap, which could enhance its antiviral activity against the COVID-19 virus.


Subject(s)
Amides , Antiviral Agents , COVID-19 Drug Treatment , Molecular Docking Simulation , Pyrazines , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Pyrazines/chemistry , Pyrazines/pharmacology , Amides/chemistry , Amides/pharmacology , SARS-CoV-2/drug effects , Humans , Density Functional Theory , Protein Binding
18.
Methods Enzymol ; 698: 57-88, 2024.
Article in English | MEDLINE | ID: mdl-38886040

ABSTRACT

Efficient and precise chemical protein modification methods are highly sought after in biotechnology. However, chemically distinguishing a single site within a large protein is challenging. This study introduces a Copper Assisted Sequence-specific Conjugation Tag (CAST) method, enabling rapid (second order rate 8.1 M-1s-1) and site-specific chemical modification of the protein backbone with pinpoint accuracy. The versatility of this method is demonstrated through the preparation of antibody-drug conjugates, showcasing high plasma stability and potent efficacy in both in vitro and in vivo settings. Thus, CAST emerges as an efficient and quantitative approach for attaching payloads to large, native proteins.


Subject(s)
Amides , Immunoconjugates , Immunoconjugates/chemistry , Amides/chemistry , Humans , Animals , Copper/chemistry , Proteins/chemistry
19.
J Infect Public Health ; 17(7): 102471, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38865775

ABSTRACT

BACKGROUND: Neutralizing monoclonal antibodies (NMabs) are recognized for their efficacy against non-severe COVID-19. However, spike protein mutations may confer resistance. This study evaluates the effectiveness of favipiravir (FPV) versus NMabs in preventing severe COVID-19 in special populations. METHODS: A retrospective cohort was conducted on middle-aged, elderly, diabetic, or obese patients with COVID-19 treated with either FPV or NMabs. Propensity score matching (PSM) was used for analysis. RESULTS: The study included 1410 patients, resulting in four cohorts: middle-aged (36), elderly (48), diabetic (46), and obese (28) post-PSM. No significant differences were noted in 28-day emergency department (ED) visits across all groups between NMabs and FPV treatments, despite lower immunity in the FPV group. However, the diabetic group treated with FPV had higher 28-day hospitalization and oxygen supplemental, with no differences in the other groups. Intensive care unit (ICU) admissions, invasive mechanical ventilation, and mortality rates were similar between the two treatments. CONCLUSIONS: Early dose-adjusted FPV showed no difference from NMabs in preventing ED visits, ICU admissions, ventilator needs, or mortality among patients with major comorbidities. Diabetic patients on FPV experienced higher hospitalizations and oxygen needs, with no observed differences in other groups. FPV may be a viable alternative, especially in settings with limited resources.


Subject(s)
Amides , Antibodies, Monoclonal , Antibodies, Neutralizing , Antiviral Agents , COVID-19 Drug Treatment , COVID-19 , Pyrazines , SARS-CoV-2 , Humans , Amides/therapeutic use , Pyrazines/therapeutic use , Middle Aged , Male , Female , Retrospective Studies , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/therapeutic use , SARS-CoV-2/immunology , Antiviral Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , COVID-19/immunology , Hospitalization/statistics & numerical data , Obesity , Outpatients , Diabetes Mellitus/drug therapy , Adult
20.
Luminescence ; 39(6): e4792, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38845344

ABSTRACT

Favipiravir (FVP) is an oral antiviral drug approved in 2021 for the treatment of COVID-19. It is a pyrazine derivative that can be integrated into anti-viral RNA products to inhibit viral replication. While, adenine is a purine nucleobase that is found in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to generate genetic information. For the first time, the binding mechanism between FVP and adenine was determined using different techniques, including UV-visible spectrophotometry, spectrofluorimetry, synchronous fluorescence (SF) spectroscopy, Fourier transform infrared (FTIR), fluorescence resonance energy transfer (FRET), and metal ion complexation. The fluorescence spectra indicated that FVP is bound to adenine via Van der Waals forces and hydrogen bonding through a spontaneous binding process (ΔGο < 0). The quenching mechanism was found to be static. Various temperature settings were used to investigate thermodynamic characteristics, such as binding forces, binding constants, and the number of binding sites. The reaction parameters, including the enthalpy change (ΔHο) and entropy change (ΔSο), were calculated using Van't Hoff's equation. The findings demonstrated that the adenine-FVP binding was endothermic. Furthermore, the results of the experiments revealed that some metal ions (K+, Ca+2, Co+2, Cu+2, and Al+3) might facilitate the binding interaction between FVP and adenine. Slight changes are observed in the FTIR spectra of adenine, indicating the binding interaction between adenine and FVP. This study may be useful in understanding the pharmacokinetic characteristics of FVP and how the drug binds to adenine to prevent any side effects.


Subject(s)
Adenine Nucleotides , Amides , Antiviral Agents , Pyrazines , Thermodynamics , Pyrazines/chemistry , Pyrazines/metabolism , Amides/chemistry , Amides/metabolism , Adenine Nucleotides/chemistry , Adenine Nucleotides/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/metabolism , Spectroscopy, Fourier Transform Infrared , Spectrometry, Fluorescence , Fluorescence Resonance Energy Transfer , Spectrophotometry, Ultraviolet , Binding Sites , Adenine/chemistry , Adenine/metabolism
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