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1.
Viruses ; 15(4)2023 04 19.
Article in English | MEDLINE | ID: mdl-37112982

ABSTRACT

The unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, and its highly transmissible variants, led to massive human suffering, death, and economic devastation worldwide. Recently, antibody-evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. Therefore, the continued development of novel drugs with pan-coronavirus inhibition is critical to treat and prevent infection of COVID-19 and any new pandemics that may emerge. We report the discovery of several highly potent small-molecule inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI > 900), suggesting its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron), and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron), SARS-CoV-1, and MERS-CoV by plaque reduction in Calu-3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Humans , SARS-CoV-2 , Anti-Retroviral Agents , Spike Glycoprotein, Coronavirus/genetics
2.
RSC Adv ; 11(5): 2664-2676, 2021 Jan 11.
Article in English | MEDLINE | ID: mdl-35424222

ABSTRACT

Alzheimer's disease is linked to the aggregation of the amyloid-ß protein (Aß) of 40 or 42 amino acids. Lipid membranes are known to modulate the rate and mechanisms of the Aß aggregation. Point mutations in Aß can alter these rates and mechanisms. In particular, experiments show that F19 mutations influence the aggregation rate, but maintain the fibril structures. Here, we used molecular dynamics simulations to examine the effect of the F19W mutation in the 3Aß11-40 trimer immersed in DPPC lipid bilayers submerged in aqueous solution. Substituting Phe by its closest (non-polar) aromatic amino acid Trp has a dramatic reduction in binding affinity to the phospholipid membrane (measured with respect to the solvated protein) compared to the wild type: the binding free energy of the protein-DPPC lipid bilayer increases by 40-50 kcal mol-1 over the wild-type. This is accompanied by conformational changes and loss of salt bridges, as well as a more complex free energy surface, all indicative of a more flexible and less stable mutated trimer. These results suggest that the impact of mutations can be assessed, at least partially, by evaluating the interaction of the mutated peptides with the lipid membranes.

3.
Case Rep Cardiol ; 2020: 8832578, 2020.
Article in English | MEDLINE | ID: mdl-33014474

ABSTRACT

Left ventricular free wall rupture is a fatal complication of acute myocardial infarction. Emergency surgical repair is usually indicated to treat this condition. However, in very high surgical risk cohort, conservative treatment can also be considered. We report a case of left ventricle pseudoaneurysm that was successfully treated conservatively in a 4-year period.

4.
Biochem Biophys Res Commun ; 498(2): 296-304, 2018 03 29.
Article in English | MEDLINE | ID: mdl-28917842

ABSTRACT

Biomolecules are complex machines that are optimized by evolution to properly fulfill or contribute to a variety of biochemical tasks in the cellular environment. Computer simulations based on quantum mechanics and atomistic force fields have been proven to be a powerful microscope for obtaining valuable insights into many biological, physical, and chemical processes. Many interesting phenomena involve, however, a time scale and a number of degrees of freedom, notably if crowding is considered, that cannot be explored at an atomistic resolution. To bridge the gap between reality and simulation, many different advanced computational techniques and coarse-grained (CG) models have been developed. Here, we report some applications of the CG OPEP protein model to amyloid fibril formation, the response of catch-bond proteins to two types of fluid flow, and interactive simulations to fold peptides with well-defined 3D structures or with intrinsic disorder.


Subject(s)
Amyloid beta-Peptides/chemistry , Models, Molecular , Adhesins, Escherichia coli/chemistry , Adhesins, Escherichia coli/metabolism , Amyloid beta-Peptides/metabolism , Escherichia coli Proteins/chemistry , Escherichia coli Proteins/metabolism , Fimbriae Proteins/chemistry , Fimbriae Proteins/metabolism , Molecular Dynamics Simulation , Monte Carlo Method , Protein Folding
5.
J Chem Phys ; 144(20): 205103, 2016 May 28.
Article in English | MEDLINE | ID: mdl-27250331

ABSTRACT

Coarse-grained protein lattice models approximate atomistic details and keep the essential interactions. They are, therefore, suitable for capturing generic features of protein folding and amyloid formation at low computational cost. As our aim is to study the critical nucleus sizes of two experimentally well-characterized peptide fragments Aß16-22 and Aß37-42 of the full length Aß1-42 Alzheimer's peptide, it is important that simulations with the lattice model reproduce all-atom simulations. In this study, we present a comprehensive force field parameterization based on the OPEP (Optimized Potential for Efficient protein structure Prediction) force field for an on-lattice protein model, which incorporates explicitly the formation of hydrogen bonds and directions of side-chains. Our bottom-up approach starts with the determination of the best lattice force parameters for the Aß16-22 dimer by fitting its equilibrium parallel and anti-parallel ß-sheet populations to all-atom simulation results. Surprisingly, the calibrated force field is transferable to the trimer of Aß16-22 and the dimer and trimer of Aß37-42. Encouraged by this finding, we characterized the free energy landscapes of the two decamers. The dominant structure of the Aß16-22 decamer matches the microcrystal structure. Pushing the simulations for aggregates between 4-mer and 12-mer suggests a nucleus size for fibril formation of 10 chains. In contrast, the Aß37-42 decamer is largely disordered with mixed by parallel and antiparallel chains, suggesting that the nucleus size is >10 peptides. Our refined force field coupled to this on-lattice model should provide useful insights into the critical nucleation number associated with neurodegenerative diseases.


Subject(s)
Amyloid/chemistry , Models, Molecular , Peptide Fragments/chemistry , Humans , Protein Folding
6.
J Immunol ; 193(7): 3278-87, 2014 Oct 01.
Article in English | MEDLINE | ID: mdl-25156366

ABSTRACT

Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making JAK inhibition an appealing strategy for the treatment of psoriasis. In this study, we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose dependently (1 nM-10 µM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild-type mice with SAR-20347 significantly reduced IL-12-induced IFN-γ production and IL-22-dependent serum amyloid A to similar extents, indicating that, in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes and proinflammatory cytokine levels compared with both TYK2 mutant mice and wild-type controls. Taken together, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis.


Subject(s)
Dermatitis/drug therapy , Interleukin-17/immunology , Interleukin-23/immunology , Interleukins/immunology , Janus Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Psoriasis/drug therapy , Signal Transduction/drug effects , TYK2 Kinase/antagonists & inhibitors , Animals , Dermatitis/genetics , Dermatitis/immunology , Dermatitis/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-12/genetics , Interleukin-12/immunology , Interleukin-17/genetics , Interleukin-23/genetics , Interleukins/genetics , Janus Kinase 1/genetics , Janus Kinase 1/immunology , Mice , Mice, Mutant Strains , Psoriasis/genetics , Psoriasis/immunology , Psoriasis/pathology , Serum Amyloid A Protein/genetics , Serum Amyloid A Protein/immunology , Signal Transduction/genetics , Signal Transduction/immunology , TYK2 Kinase/genetics , TYK2 Kinase/immunology , Interleukin-22
7.
Curr HIV Res ; 7(6): 639-49, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19929801

ABSTRACT

Despite availability of successful prevention strategies, HIV continues to spread at alarming rates, especially among women in developing countries. Vaginal microbicides offer a promising approach for blocking transmission of HIV when condom use cannot be negotiated with male partners. A major problem in the development of vaginal microbicides is chemically induced vaginal irritation, which can enhance the risk of HIV transmission. Evaluation of vaginal irritation prior to clinical trials typically uses an expensive and animal-intensive rabbit vaginal irritation model, which could be supplemented by measuring additional inflammatory biomarkers. We studied several immunological parameters as potential biomarkers of vaginal irritation, using the spermicides nonoxynol-9 and benzalkonium chloride as test microbicides. We measured amounts of cytokines, as well as inflammatory cells, in vaginal tissue lysates and on the vaginal surface. We observed that treatment with the selected microbicides increases quantities of the inflammatory cytokines interleukin-1beta, CXCL8, and CCL2 in the vaginal tissue parenchyma, and of CCL2 on the vaginal surface. This observation was correlated with increases in macrophages in the vaginal parenchyma. We suggest that measurements of CCL2 and macrophages can serve as new inflammatory biomarkers to evaluate the safety of promising novel microbicides for prevention of HIV.


Subject(s)
Benzalkonium Compounds/adverse effects , Cell Movement/drug effects , Chemokine CCL2/biosynthesis , Inflammation/immunology , Macrophages/drug effects , Monocytes/drug effects , Nonoxynol/adverse effects , Surface-Active Agents/adverse effects , Vagina/drug effects , Animals , Biomarkers , Chemokine CCL2/immunology , Female , HIV/drug effects , HIV Infections/immunology , HIV Infections/prevention & control , HIV Infections/virology , Humans , Inflammation/metabolism , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Interleukin-8/biosynthesis , Interleukin-8/immunology , Macrophages/physiology , Monocytes/physiology , Rabbits , Vagina/pathology , Vagina/physiology
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