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Nanomedicine : Nanotechnology, Biology,... Jan 2023In a context of drug repurposing, pentamidine (PTM), an FDA-approved antiparasitic drug, has been proposed to reverse the splicing defects associated in myotonic...
In a context of drug repurposing, pentamidine (PTM), an FDA-approved antiparasitic drug, has been proposed to reverse the splicing defects associated in myotonic dystrophy type 1 (DM1). However, clinical use of PTM is hinder by substantial toxicity, leading to find alternative delivery strategies. In this work we proposed hyaluronic acid-based nanoparticles as a novel encapsulation strategy to efficiently deliver PTM to skeletal muscles cells. In vitro studies on C2C12 myoblasts and myotubes showed an efficient nanoparticles' internalization with minimal toxicity. More interestingly, our findings evidenced for the first time the endosomal escape of hyaluronic acid-based nanocarriers. Ex vivo studies showed an efficient nanoparticles' internalization within skeletal muscle fibers. Finally, the therapeutic efficacy of PTM-loaded nanosystems to reduce the number of nuclear foci has been demonstrated in a novel DM1 in vitro model. So far, current data demonstrated the potency of hyaluronic acid-based nanosystems as efficient nanocarrier for delivering PTM into skeletal muscle and mitigate DM1 pathology.
Topics: Humans; Myotonic Dystrophy; Pentamidine; Hyaluronic Acid; Muscle, Skeletal
PubMed: 36309185
DOI: 10.1016/j.nano.2022.102623 -
Pathogens (Basel, Switzerland) Sep 2022Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of... (Review)
Review
Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0−91.6); I2 = 96.99% (95% CI: 94.6−98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94−59.09) and 6.56% (3.06−11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.
PubMed: 36297157
DOI: 10.3390/pathogens11101100 -
ACS Chemical Biology Nov 2022Most Gram-positive-selective antibiotics have low activity against Gram-negative bacteria due to the presence of an outer membrane barrier. There is, therefore, interest...
Most Gram-positive-selective antibiotics have low activity against Gram-negative bacteria due to the presence of an outer membrane barrier. There is, therefore, interest in developing combination therapies that can penetrate the outer membrane (OM) with known antibiotics coupled with membrane-active sensitizing adjuvants. However, two unanswered questions hinder the development of such combination therapies: the sensitization spectrum of the sensitizer and the mechanism of antibiotic-sensitizer mutual potentiation. Here, with pentamidine as an example, we screened a library of 170 FDA-approved antibiotics in combination with pentamidine, a compound known to disturb the OM of Gram-negative bacteria. We found that four antibiotics, minocycline, linezolid, valnemulin, and nadifloxacin, displaced enhanced activity in combination with pentamidine against several multidrug-resistant Gram-negative bacteria. Through a descriptor-based structural-activity analysis and multiple cell-based biochemical assays, we found that hydrophobicity, partial charge, rigidity, and surface rugosity were key factors that affected sensitization via a cooperative membrane damage mechanism in which lipopolysaccharides and phospholipids were identified as sites of synergy. Finally, experiments showed that the linezolid-pentamidine combination slowed the generation of drug resistance, and there was also potent activity in experiments. Overall, our results highlight the importance of the physicochemical properties of antibiotics and cooperative membrane damage for synergistic pentamidine-antibiotic drug combinations.
Topics: Anti-Bacterial Agents; Pentamidine; Linezolid; Gram-Negative Bacteria; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests
PubMed: 36269311
DOI: 10.1021/acschembio.2c00613 -
Antimicrobial Agents and Chemotherapy Nov 2022The purpose of this single-center retrospective case series was to evaluate the efficacy and safety of 300-mg once-monthly intravenous (IV) pentamidine prophylaxis in...
The purpose of this single-center retrospective case series was to evaluate the efficacy and safety of 300-mg once-monthly intravenous (IV) pentamidine prophylaxis in 702 adult allogeneic hematopoietic stem cell transplant (HSCT) patients. We observed no cases of Pneumocystis jirovecii pneumonia (PJP) following IV pentamidine administration. Breakthrough and infections were observed in 7 (1%) and 5 (0.7%) patients, respectively. The most commonly reported adverse event was nausea. Monthly IV pentamidine is a reasonable alternative to trimethoprim-sulfamethoxazole (TMP-SMX).
Topics: Humans; Adult; Pneumonia, Pneumocystis; Pentamidine; Pneumocystis carinii; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 36214573
DOI: 10.1128/aac.00833-22 -
Biomedical Chromatography : BMC Jul 2023Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to... (Review)
Review
Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to conduct pharmacokinetic (PK) analysis. This review provides a comprehensive overview of published validated bioanalytical assays for the quantification of antileishmanial drugs amphotericin B, miltefosine, paromomycin, pentamidine, and pentavalent antimonials in human matrices. The applicability of the assays for leishmaniasis clinical trials as well as their relevance to PK studies with emphasis on the choice of matrix, calibration range, sample volume, sample preparation, choice of internal standards, separation, and detection was discussed for each antileishmanial drug. Given that no published bioanalytical methods included multiple antileishmanial drugs in a single assay although antileishmanial shortened combination regimens currently were under investigation, it was recommended to combine various drugs in a single bioanalytical method. Furthermore, bioanalytical method development regarding target site matrix as well as applying microsampling strategies was recommended to optimize future clinical PK studies in leishmaniasis.
Topics: Humans; Antiprotozoal Agents; Pentamidine; Leishmaniasis; Amphotericin B
PubMed: 36208186
DOI: 10.1002/bmc.5519 -
Journal of the American Chemical Society Sep 2022The first non-uranyl, f-element oxo complex synthesized from dioxygen in dry air is presented in this work. The synthesis was accomplished by treating the redox-active...
The first non-uranyl, f-element oxo complex synthesized from dioxygen in dry air is presented in this work. The synthesis was accomplished by treating the redox-active thorium amidophenolate complex, [Th(ap)][K(15--5)] (), with dioxygen in dry air, forming a rare terminal thorium oxo, [O═Th(isq)(ap)][K(15--5)] (). Compound was regenerated by treating with potassium graphite. X-ray crystallography of revealed a comparatively longer bond length for the thorium-oxygen double bond when compared to other thorium oxos. As such, several thorium-oxygen single bonds were synthesized for comparison, including Th(isq)(OSiMe)(THF) (), Th(OSiMe)(bipy) (), and [Th(OH) (Hap)][K(15--5)] (). Full spectroscopic and structural characterization of the complexes was performed via H NMR spectroscopy, X-ray crystallography, EPR spectroscopy, and electronic absorption spectroscopy as well as SQUID magnetometry, which all confirmed the electronic structure of these complexes.
Topics: Graphite; Ligands; Oxidation-Reduction; Oxygen; Pentamidine; Potassium; Thorium
PubMed: 36122408
DOI: 10.1021/jacs.2c04947 -
ChemMedChem Nov 2022There is an emerging interest in utilizing synthetic multivalent inhibitors that comprise of multiple inhibitor moieties linked on a common scaffold to achieve strong...
There is an emerging interest in utilizing synthetic multivalent inhibitors that comprise of multiple inhibitor moieties linked on a common scaffold to achieve strong and selective enzyme inhibition. As multivalent inhibition is impacted by valency and linker length, in this study, we explore the effect of multivalent benzamidine inhibitors of varying valency and linker length on plasmin inhibition. Plasmin is an endogenous enzyme responsible for digesting fibrin present in blood clots. Monovalent plasmin(ogen) inhibitors are utilized clinically to treat hyperfibrinolysis-associated bleeding events. Benzamidine is a reversible inhibitor that binds to plasmin's active site. Herein, multivalent benzamidine inhibitors of varying valencies (mono-, bi- and tri-valent) and linker lengths (∼1-12 nm) were synthesized to systematically study their effect on plasmin inhibition. Inhibition assays were performed using a plasmin substrate (S-2251) to determine inhibition constants (Ki). Pentamidine (shortest bivalent) and Tri-AMB (shortest trivalent) were the strongest inhibitors with Ki values of 2.1±0.8 and 3.9±1.7 μM, respectively. Overall, increasing valency and decreasing linker length, increases effective local concentration of the inhibitor and therefore, resulted in stronger inhibition of plasmin via statistical rebinding. This study aids in the design of multivalent inhibitors that can achieve desired enzyme inhibition by means of modulating valency and linker length.
Topics: Fibrinolysin; Benzamidines
PubMed: 36111842
DOI: 10.1002/cmdc.202200364 -
International Journal of Pharmaceutics Sep 2022Pentamidine (PTM) is an aromatic diamidine approved for the treatment of parasitic infections that has been recently proposed for possible repositioning as an anticancer...
Pentamidine (PTM) is an aromatic diamidine approved for the treatment of parasitic infections that has been recently proposed for possible repositioning as an anticancer drug. To this aim, efforts have been made to improve its therapeutic efficacy and reduce associated adverse effects through both covalent derivatization and association with nanocarriers. To efficiently encapsulate PTM into biocompatible nanoparticles and to enhance its selectivity toward cancer cells, a squalene (SQ) derivative (1,1',2-tris-norsqualenoic acid, SQ-COOH) was selected to prepare PTM-loaded nanocarriers. Indeed, SQ and its derivatives self-assemble into nanoparticles in aqueous media. Furthermore, SQ-bioconjugates strongly interact with low-density lipoproteins (LDL), thus favoring preferential accumulation in cells overexpressing the LDL receptor (LDLR). We report here the preparation of nanocarriers by ion-pairing between the negatively charged SQ-COOH and the positively charged PTM free base (PTM-B), which allowed the covalent grafting of SQ to PTM to be avoided. The nanoparticles were characterized (mean size < 200 nm and zeta potential < -20 mV for SQ-COOH/PTM-B 3:1 molar ratio) and molecular modelling studies of the SQ-COOH/PTM-B interaction confirmed the nanocarrier stability. Finally, the ability to indirectly target LDLR-overexpressing cancer cells was evaluated by in vitro cell viability assays and confirmed by LDLR silencing, serum privation and simvastatin treatment.
Topics: Antineoplastic Agents; Cell Survival; Drug Carriers; Nanoparticles; Neoplasms; Pentamidine; Squalene
PubMed: 35961419
DOI: 10.1016/j.ijpharm.2022.122102 -
The New Phytologist Nov 2022Sugars are essential metabolites for energy and anabolism that can also act as signals to regulate plant physiology and development. Experimental tools to disrupt major...
Sugars are essential metabolites for energy and anabolism that can also act as signals to regulate plant physiology and development. Experimental tools to disrupt major sugar signalling pathways are limited. We performed a chemical screen for modifiers of activation of circadian gene expression by sugars to discover pharmacological tools to investigate and manipulate plant sugar signalling. Using a library of commercially available bioactive compounds, we identified 75 confident hits that modified the response of a circadian luciferase reporter to sucrose in dark-adapted Arabidopsis thaliana seedlings. We validated the transcriptional effect on a subset of the hits and measured their effects on a range of sugar-dependent phenotypes for 13 of these chemicals. Chemicals were identified that appear to influence known and unknown sugar signalling pathways. Pentamidine isethionate was identified as a modifier of a sugar-activated Ca signal that acts as a calmodulin inhibitor downstream of superoxide in a metabolic signalling pathway affecting circadian rhythms, primary metabolism and plant growth. Our data provide a resource of new experimental tools to manipulate plant sugar signalling and identify novel components of these pathways.
Topics: Arabidopsis; Arabidopsis Proteins; Calmodulin; Carbohydrates; Circadian Rhythm; Gene Expression; Gene Expression Regulation, Plant; Pentamidine; Reactive Oxygen Species; Sucrose; Sugars; Superoxides
PubMed: 35842791
DOI: 10.1111/nph.18380 -
Human Molecular Genetics Jan 2023DNA drug molecules are not only widely used in gene therapy, but also play an important role in controlling the electrical properties of molecular electronics. Covalent...
DNA drug molecules are not only widely used in gene therapy, but also play an important role in controlling the electrical properties of molecular electronics. Covalent binding, groove binding and intercalation are all important forms of drug-DNA interaction. But its applications are limited due to a lack of understanding of the electron transport mechanisms after different drug-DNA interaction modes. Here, we used a combination of density functional theory calculations and nonequilibrium Green's function formulation with decoherence to study the effect of drug molecules on the charge transport property of DNA under three different binding modes. Conductance of DNA is found to decrease from 2.35E-5 G0 to 1.95E-6 G0 upon doxorubicin intercalation due to modifications of the density of states in the near-highest occupied molecular orbital region, δG = 1105.13%. Additionally, the conductance of DNA after cis-[Pt(NH3)2(py)Cl]+ covalent binding increases from 1.02E-6 G0 to 5.25E-5 G0, δG = 5047.06%. However, in the case of pentamidine groove binding, because there is no direct change in DNA molecular structure during drug binding, the conductance changes before and after drug binding is much smaller than in the two above cases, δG = 90.43%. Our theoretical calculations suggest that the conductance of DNA can be regulated by different drug molecules or switching the interaction modes between small molecules and DNA. This regulation opens new possibilities for their potential applications in controllable modulation of the electron transport property of DNA.
Topics: DNA; Electron Transport
PubMed: 35771227
DOI: 10.1093/hmg/ddac147