Halogen bonding triggers activity: Increasing binding affinity was observed for a series of covalent human Cathepsin L inhibitors by exchanging an aryl ring H atom with Cl, Br, and I, which undergo ...halogen bonding with the CO group of Gly61 in the S3 pocket of the enzyme. Fluorine, in contrast, strongly avoids halogen bonding (see scheme). The strong distance and angle dependence of halogen bonding was confirmed for biological systems.
Nanoscale surface roughness has been suggested to have antibacterial and antifouling properties. Several existing models have attempted to explain the antibacterial mechanism of nanoscale rough ...surfaces without direct observation. Here, conventional and liquid-cell TEM are implemented to observe nanoscale bacteria/surface roughness interaction. The visualization of such interactions enables the inference of possible antibacterial mechanisms.
Nanotextures are synthesized on biocompatible polymer microparticles (MPs) via plasma etching. Both conventional and liquid-phase transmission electron microscopy observations suggest that these MPs may cause cell lysis via bacterial binding to a single protrusion of the nanotexture. The bacterium/protrusion interaction locally compromises the cell wall, thus causing bacterial death. This study suggests that local mechanical damage and leakage of the cytosol kill the bacteria first, with subsequent degradation of the cell envelope.
Nanoscale surface roughness may act via a penetrative bactericidal mechanism. This insight suggests that future research may focus on optimizing bacterial binding to individual nanoscale projections in addition to stretching bacteria between nanopillars. Further, antibacterial nanotextures may find use in novel applications employing particles in addition to nanotextures on fibers or films.
Calcium oxalate (CaOx) is the major phase in kidney stones and the primary calcium storage medium in plants. CaOx can form crystals with different lattice types, water contents, and crystal ...structures. However, the conditions and mechanisms leading to nucleation of particular CaOx crystals are unclear. Here, liquid‐cell transmission electron microscopy and atomistic molecular dynamics simulations are used to study in situ CaOx nucleation at different conditions. The observations reveal that rhombohedral CaOx monohydrate (COM) can nucleate via a classical pathway, while square COM can nucleate via a non‐classical multiphase pathway. Citrate, a kidney stone inhibitor, increases the solubility of calcium by forming calcium‐citrate complexes and blocks oxalate ions from approaching calcium. The presence of multiple hydrated ionic species draws additional water molecules into nucleating CaOx dihydrate crystals. These findings reveal that by controlling the nucleation pathways one can determine the macroscale crystal structure, hydration state, and morphology of CaOx.
Liquid‐cell transmission electron microscopy and molecular dynamic simulations compare the nanoscale formation pathways of calcium oxalate (CaOx) in the absence or presence of citrate. In the absence of citrate, CaOx forms a rhombohedral morphology via the classical crystallization pathway. Square CaOx monohydrate forms via a nonclassical pathway. The presence of citrate inhibits the formation of CaOx and promotes formation of CaOx dihydrate.
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of ...their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer’s disease treatment.
Fluorine in Medicinal Chemistry Böhm, Hans-Joachim; Banner, David; Bendels, Stefanie ...
Chembiochem : a European journal of chemical biology,
May 3, 2004, Letnik:
5, Številka:
5
Journal Article
Recenzirano
Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed ...strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D‐structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein–ligand interactions that involve fluorine.
Bring on the substitute. Our continuously improving understanding of the diverse physicochemical, biophysical, and pharmacological effects of H/F substitution offers interesting new opportunities in medicinal chemistry; for example, the thrombin inhibitor shown here in orange is six times more potent than its non‐fluorinated analogue.
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pK a and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 ...substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
Severe influenza remains a major public health threat and is responsible for thousands of deaths annually. Increasing antiviral resistance and limited effectiveness of current therapies highlight the ...need for new approaches to influenza treatment. Extensive pre-clinical data have shown that mesenchymal stromal (stem) cell (MSC) therapy can induce anti-inflammatory effects and enhance repair of the injured lung. We hypothesized that MSC therapy would improve survival, dampen lung inflammation and decrease acute lung injury (ALI) in a murine model of severe influenza.
C57Bl/6 mice were infected with influenza A/PuertoRico/8/34 (mouse-adapted H1N1) or influenza A/Mexico/4108/2009 (swine-origin pandemic H1N1) and administered human or mouse MSCs via the tail vein, either pre- or post- infection. MSC efficacy was evaluated as both an independent and adjunctive treatment strategy in combination with the antiviral agent, oseltamivir. Weight loss and survival were monitored. Inflammatory cells, cytokine/chemokines (IFN-γ, CXCL10, CCL2 and CCL5) and markers of ALI (total protein and IgM), were measured in bronchoalveolar lavage fluid and lung parenchyma.
Administration of murine MSCs or human MSCs in a prophylactic or therapeutic regimen failed to improve survival, decrease pulmonary inflammation/inflammatory cell counts or prevent ALI in influenza virus-infected mice. MSCs administered in combination with oseltamivir also failed to improve outcomes.
Despite similarities in the clinical presentation and pathobiology of ALI and severe influenza, our findings suggest that MSC therapy may not be effective for prevention and/or treatment of acute severe influenza.
Seasonal influenza viruses are typically restricted to the human upper respiratory tract whereas influenza viruses with greater pathogenic potential often also target extra-pulmonary organs. Infants, ...pregnant women, and breastfeeding mothers are highly susceptible to severe respiratory disease following influenza virus infection but the mechanisms of disease severity in the mother-infant dyad are poorly understood. Here we investigated 2009 H1N1 influenza virus infection and transmission in breastfeeding mothers and infants utilizing our developed infant-mother ferret influenza model. Infants acquired severe disease and mortality following infection. Transmission of the virus from infants to mother ferrets led to infection in the lungs and mother mortality. Live virus was also found in mammary gland tissue and expressed milk of the mothers which eventually led to milk cessation. Histopathology showed destruction of acini glandular architecture with the absence of milk. The virus was localized in mammary epithelial cells of positive glands. To understand the molecular mechanisms of mammary gland infection, we performed global transcript analysis which showed downregulation of milk production genes such as Prolactin and increased breast involution pathways indicated by a STAT5 to STAT3 signaling shift. Genes associated with cancer development were also significantly increased including JUN, FOS and M2 macrophage markers. Immune responses within the mammary gland were characterized by decreased lymphocyte-associated genes CD3e, IL2Ra, CD4 with IL1β upregulation. Direct inoculation of H1N1 into the mammary gland led to infant respiratory infection and infant mortality suggesting the influenza virus was able to replicate in mammary tissue and transmission is possible through breastfeeding. In vitro infection studies with human breast cells showed susceptibility to H1N1 virus infection. Together, we have shown that the host-pathogen interactions of influenza virus infection in the mother-infant dyad initiate immunological and oncogenic signaling cascades within the mammary gland. These findings suggest the mammary gland may have a greater role in infection and immunity than previously thought.
In two series of small‐molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors ...is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X‐ray co‐crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone CO in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein–ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (CarylX) and the XB acceptor (CO) in the correct geometry. New X‐ray co‐crystal structures in the same crystal form (space group P212121) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high‐resolution structures reveal that the backbone CO group of Gly61 in most hcatL co‐crystal structures maintains water solvation while engaging in XB. An arylCF3‐substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the CO group of Gly61 in the S3 pocket. In this case, a repulsive F2CF⋅⋅⋅OC contact apparently is energetically overcompensated by other favorable protein–ligand contacts established by the CF3 group.
Halogen‐ius! X‐ray co‐crystal structures of inhibitors undergoing halogen bonding in the water‐exposed S3 pocket of human cathepsin L and the apolar back pocket of MEK1 kinase are analyzed (see figure). A similar affinity trend is observed for both polar and apolar environments.
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