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Molecules (Basel, Switzerland) Aug 2015Non-covalent derivatives (NCDs) are formed by incorporating one (or more) coformer molecule(s) into the matrix of a parent molecule via non-covalent forces. These forces... (Review)
Review
Non-covalent derivatives (NCDs) are formed by incorporating one (or more) coformer molecule(s) into the matrix of a parent molecule via non-covalent forces. These forces can include ionic forces, Van der Waals forces, hydrogen bonding, lipophilic-lipophilic interactions and pi-pi interactions. NCDs, in both cocrystal and eutectic forms, possess properties that are unique to their supramolecular matrix. These properties include critical product performance factors such as solubility, stability and bioavailability. NCDs have been used to tailor materials for a variety of applications and have the potential to be used in an even broader range of materials and processes. NCDs can be prepared using little or no solvent and none of the reagents typical to synthetic modifications. Thus, NCDs represent a powerfully versatile, environmentally-friendly and cost-effective opportunity.
Topics: Agrochemicals; Cosmetics; Crystallization; Food Additives; Temperature
PubMed: 26287141
DOI: 10.3390/molecules200814833 -
The AAPS Journal Jan 2015Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal... (Review)
Review
Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal antibodies are quite similar with respect to their developability properties. However, the properties of therapeutic peptides tend to be as diverse as the molecules themselves. Analysis of the primary sequence reveals sites of potential adverse posttranslational modifications including asparagine deamidation, aspartic acid isomerization, methionine, tryptophan, and cysteine oxidation and, potentially, chemical and proteolytic degradation liabilities that can impact the developability and manufacturability of a potential therapeutic peptide. Assessing these liabilities, both biophysically and functionally, early in a molecule's lifetime can drive a more effective path forward in the drug discovery process. In addition to these potential liabilities, more complex peptides that contain multiple disulfide bonds can pose particular challenges with respect to production and manufacturability. Approaches to reducing the disulfide bond complexity of these peptides are often explored with mixed success. Proteolytic degradation is a major contributor to decreased half-life and efficacy. Addressing this aspect of peptide stability early in the discovery process increases downstream success. We will address aspects of peptide sequence analysis, molecule complexity, developability analysis, and manufacturing routes that drive the decision making processes during peptide therapeutic development.
Topics: Antibodies, Monoclonal; Drug Design; Half-Life; Humans; Peptides; Protein Engineering; Protein Processing, Post-Translational; Protein Stability; Sequence Analysis
PubMed: 25338742
DOI: 10.1208/s12248-014-9681-9 -
Sensors (Basel, Switzerland) Aug 2023A 1,2,3-triazole-based chemosensor is used for selective switching in logic gate operations through colorimetric and fluorometric response mechanisms. The molecular...
A 1,2,3-triazole-based chemosensor is used for selective switching in logic gate operations through colorimetric and fluorometric response mechanisms. The molecular probe synthesized via "click chemistry" resulted in a non-fluorescent 1,4-diaryl-1,2,3-triazole with a phenol moiety (). However, upon sensing fluoride, it TURNS ON the molecule's fluorescence. The TURN-OFF order occurs through fluorescence quenching of the sensor when metal ions, e.g., Cu, and Zn, are added to the -fluoride ensemble. A detailed characterization using Nuclear Magnetic Resonance (NMR) spectroscopy in a sequential titration study substantiated the photophysical characteristics of through UV-Vis absorption and fluorescence profiles. A combination of fluorescence OFF-ON-OFF sequences provides evidence of 1,2,3-triazoles being controlled switches applicable to multimodal logic operations. The "INH" gate was constructed based on the fluorescence output of when the inputs are F and Zn. The "IMP" and "OR" gates were created on the colorimetric output responses using the probe's absorption with multiple inputs (F and Zn or Cu). The sensor is the best example of the "Write-Read-Erase-Read" mimic.
PubMed: 37571784
DOI: 10.3390/s23157000 -
Journal of Orthopaedic Research :... May 2017Recent evidence suggests that common factor(s) or molecule(s) might regulate lipid and glucose metabolism, inflammation, and bone and cartilage degeneration. These... (Review)
Review
Recent evidence suggests that common factor(s) or molecule(s) might regulate lipid and glucose metabolism, inflammation, and bone and cartilage degeneration. These findings may be particularly relevant for cases of rheumatoid arthritis, in which chronic inflammation occurs in an autoimmune context and causes the degradation of articular joints as well as insulin resistance and cardiovascular complications. Candidates for this common regulatory system include signals mediated by peroxisome proliferator-activated regulator and its response factor, angiopoietin-like 4. The expression and bioactivity of angiopoietin-like 4, an adipocytokine that was originally reported to have an angiogenic function, have been detected not only in the vascular system and adipose tissue but also in rheumatoid joints. An essential role for angiopoietin-like 4 has been established in dyslipidemia, and recent reports indicate that it may modulate bone and cartilage catabolism in rheumatoid arthritis. The enhanced expression of angiopoietin-like 4 in rheumatoid arthritis may explain the occurrence of insulin resistance, cardiovascular risk, and joint destruction, thereby suggesting that this molecule could be a potential target for anti-rheumatoid arthritis strategies. This review describes recent research on the role of angiopoietin-like 4 in chronic inflammatory conditions and rheumatoid arthritis, as well as potential therapeutic candidates. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:939-943, 2017.
Topics: Angiopoietin-Like Protein 4; Angiopoietins; Arthritis, Rheumatoid; Chronic Disease; Humans; Inflammation; Insulin Resistance
PubMed: 28004425
DOI: 10.1002/jor.23507 -
Bioconjugate Chemistry Apr 2019Biomolecules have many properties that make them promising for intracellular therapeutic applications, but delivery remains a key challenge because large biomolecules... (Review)
Review
Biomolecules have many properties that make them promising for intracellular therapeutic applications, but delivery remains a key challenge because large biomolecules cannot easily enter the cytosol. Furthermore, quantification of total intracellular versus cytosolic concentrations remains demanding, and the determination of delivery efficiency is thus not straightforward. In this review, we discuss strategies for delivering biomolecules into the cytosol and briefly summarize the mechanisms of uptake for these systems. We then describe commonly used methods to measure total cellular uptake and, more selectively, cytosolic localization, and discuss the major advantages and drawbacks of each method. We critically evaluate methods of measuring "cell penetration" that do not adequately distinguish total cellular uptake and cytosolic localization, which often lead to inaccurate interpretations of a molecule's cytosolic localization. Finally, we summarize the properties and components of each method, including the main caveats of each, to allow for informed decisions about method selection for specific applications. When applied correctly and interpreted carefully, methods for quantifying cytosolic localization offer valuable insight into the bioactivity of biomolecules and potentially the prospects for their eventual development into therapeutics.
Topics: Bacterial Toxins; Biological Transport; Cell Compartmentation; Cell Membrane; Cell-Penetrating Peptides; Cytosol; DNA-Binding Proteins; Drug Delivery Systems; Humans; Liposomes; Nanoparticles; Virion; Zinc Fingers
PubMed: 30882208
DOI: 10.1021/acs.bioconjchem.9b00112 -
Molecules (Basel, Switzerland) Feb 2023For many decades, uracil has been an antineoplastic agent used in combination with tegafur to treat various human cancers, including breast, prostate, and liver cancer....
Quantum Computational, Spectroscopic (FT-IR, FT-Raman, NMR, and UV-Vis) Hirshfeld Surface and Molecular Docking-Dynamics Studies on 5-Hydroxymethyluracil (Monomer and Trimer).
For many decades, uracil has been an antineoplastic agent used in combination with tegafur to treat various human cancers, including breast, prostate, and liver cancer. Therefore, it is necessary to explore the molecular features of uracil and its derivatives. Herein, the molecule's 5-hydroxymethyluracil has been thoroughly characterized by NMR, UV-Vis, and FT-IR spectroscopy by means of experimental and theoretical analysis. Density functional theory (DFT) using the B3LYP method at 6-311++G(d,p) was computed to achieve the optimized geometric parameters of the molecule in the ground state. For further investigation and computation of the NLO, NBO, NHO analysis, and FMO, the improved geometrical parameters were utilized. The potential energy distribution was used to allocate the vibrational frequencies using the VEDA 4 program. The NBO study determined the relationship between the donor and acceptor. The molecule's charge distribution and reactive regions were highlighted using the MEP and Fukui functions. Maps of the hole and electron density distribution in the excited state were generated using the TD-DFT method and PCM solvent model in order to reveal electronic characteristics. The energies and diagrams for the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) were also provided. The HOMO-LUMO band gap estimated the charge transport within the molecule. When examining the intermolecular interactions in 5-HMU, Hirshfeld surface analysis was used, and fingerprint plots were also produced. The molecular docking investigation involved docking 5-HMU with six different protein receptors. Molecular dynamic simulation has given a better idea of the binding of the ligand with protein.
Topics: Humans; Molecular Docking Simulation; Molecular Conformation; Molecular Dynamics Simulation; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Static Electricity; Thermodynamics; Spectrophotometry, Ultraviolet; Pentoxyl; Quantum Theory
PubMed: 36903362
DOI: 10.3390/molecules28052116 -
Nature Communications Apr 2024The heterogeneity inherent in today's biotherapeutics, especially as a result of heavy glycosylation, can affect a molecule's safety and efficacy. Characterizing this...
The heterogeneity inherent in today's biotherapeutics, especially as a result of heavy glycosylation, can affect a molecule's safety and efficacy. Characterizing this heterogeneity is crucial for drug development and quality assessment, but existing methods are limited in their ability to analyze intact glycoproteins or other heterogeneous biotherapeutics. Here, we present an approach to the molecular assessment of biotherapeutics that uses proton-transfer charge-reduction with gas-phase fractionation to analyze intact heterogeneous and/or glycosylated proteins by mass spectrometry. The method provides a detailed landscape of the intact molecular weights present in biotherapeutic protein preparations in a single experiment. For glycoproteins in particular, the method may offer insights into glycan composition when coupled with a suitable bioinformatic strategy. We tested the approach on various biotherapeutic molecules, including Fc-fusion, VHH-fusion, and peptide-bound MHC class II complexes to demonstrate efficacy in measuring the proteoform-level diversity of biotherapeutics. Notably, we inferred the glycoform distribution for hundreds of molecular weights for the eight-times glycosylated fusion drug IL22-Fc, enabling correlations between glycoform sub-populations and the drug's pharmacological properties. Our method is broadly applicable and provides a powerful tool to assess the molecular heterogeneity of emerging biotherapeutics.
Topics: Glycosylation; Glycoproteins; Mass Spectrometry; Polysaccharides
PubMed: 38627419
DOI: 10.1038/s41467-024-47693-8 -
Annals of the American Thoracic Society Oct 2023It can be challenging for healthcare professionals (HCPs) to prescribe inhaled therapy for patients with chronic obstructive pulmonary disease (COPD) because of the... (Review)
Review
It can be challenging for healthcare professionals (HCPs) to prescribe inhaled therapy for patients with chronic obstructive pulmonary disease (COPD) because of the multiple individual and combinations of inhaled medications available in numerous delivery systems. Guidance on the selection of an inhaled delivery system has received limited attention compared with the emphasis on prescribing the class of the inhaled molecule(s). Although numerous recommendations and algorithms have been proposed to guide the selection of an inhaled delivery system for patients with COPD, no specific approach has been endorsed in COPD guidelines/strategies or by professional organizations. To provide recommendations for an inhaler selection strategy at initial and follow-up appointments, we examined the impact of patient errors using handheld inhalers on clinical outcomes and performed a focused narrative review to consider patient factors (continuity of the inhaled delivery system, cognitive function, manual function/dexterity, and peak inspiratory flow) when selecting an inhaled delivery system. On the basis of these findings, five questions are proposed for HCPs to consider in the initial selection of an inhaler delivery system and three questions to consider at follow-up. We propose that HCPs consider the inhaled medication delivery system as a unit and to match appropriate medication(s) with the unique features of the delivery system to individual patient factors. Assessment of inhaler technique and adherence together with patient outcomes/satisfaction at each visit is essential to determine whether the inhaled medication delivery system is providing benefits. Continued and repeated education on device features and correct technique is warranted to optimize efficacy.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Nebulizers and Vaporizers; Pharmaceutical Preparations; Patient Satisfaction; Administration, Inhalation; Bronchodilator Agents
PubMed: 37499210
DOI: 10.1513/AnnalsATS.202304-384CME -
Pharmaceutics Apr 2023Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have... (Review)
Review
Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments.
PubMed: 37111734
DOI: 10.3390/pharmaceutics15041249 -
Cardiovascular Research Jun 2015Acute and chronic inflammation responses characterize the vascular remodelling processes in atherosclerosis, restenosis, pulmonary arterial hypertension, and... (Review)
Review
Acute and chronic inflammation responses characterize the vascular remodelling processes in atherosclerosis, restenosis, pulmonary arterial hypertension, and angiogenesis. The functional and phenotypic changes in diverse vascular cell types are mediated by complex signalling cascades that initiate and control genetic reprogramming. The signalling molecule's signal transducer and activator of transcription 3 (STAT3) plays a key role in the initiation and continuation of these pathophysiological changes. This review highlights the pivotal involvement of STAT3 in pathological vascular remodelling processes and discusses potential translational therapies, which target STAT3 signalling, to prevent and treat cardiovascular diseases. Moreover, current clinical trials using highly effective and selective inhibitors of STAT3 signalling for distinct diseases, such as myelofibrosis and rheumatoid arthritis, are discussed with regard to their vascular (side-) effects and their potential to pave the way for a direct use of these molecules for the prevention or treatment of vascular diseases.
Topics: Animals; Cardiovascular Agents; Drug Discovery; Endothelial Cells; Humans; Molecular Targeted Therapy; Neovascularization, Physiologic; Regeneration; STAT3 Transcription Factor; Signal Transduction; Translational Research, Biomedical; Vascular Diseases
PubMed: 25784694
DOI: 10.1093/cvr/cvv103