Samer Al-Gharabli

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS-CoV Mpro) Inhibitors

A method for the parallel solid‐phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization‐free oxidation of amino alcohols with Dess–Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N‐protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS‐CoV Mpro(also known as 3CLpro), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS‐CoV Mpro. Several potent inhibitors were found with IC50 values in the low micromolar range. An IC50 of 7.5 μM was found for AcNSTSQ‐H and AcESTLQ‐H. Interestingly, the most potent inhibitors seem to bind to SARS‐CoV Mpro in a noncanonical binding mode.

Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease.

Abstract SARS coronavirus main protease (SARS-CoV Mpro) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV Mpro. Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV Mpro requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV Mpro in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV Mpro, with Ki values in the μM range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2=Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV Mpro in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV Mpro, with Ki =2.24±0.58μM. These results show that the stringent substrate specificity of the SARS-CoV Mpro with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.

Molecular Grafting of Fluorinated and Nonfluorinated Alkylsiloxanes on Various Ceramic Membrane Surfaces for the Removal of Volatile Organic Compounds Applying Vacuum Membrane Distillation

Four main tasks were presented: (i) ceramic membrane functionalization (TiO2 5 kDa and 300 kDa), (ii) extended material characterization (physicochemistry and tribology) of pristine and modified ceramic samples, (iii) evaluation of chemical and mechanical stability, and finally (iv) assessment of membrane efficiency in vacuum membrane distillation applied for volatile organic compounds (VOCs) removal from water. Highly efficient molecular grafting with four types of perfluoroalkylsilanes and one nonfluorinated agent was developed. Materials with controllable tribological and physicochemical properties were achieved. The most meaningful finding is associated with the applicability of fluorinated and nonfluorinated grafting agents. The results of contact angle, hysteresis of contact angle, sliding angle, and critical surface tension as well as Youngs modulus, nanohardness, and adhesion force for grafting by these two modifiers are comparable. This provides insight into the potential applicability of environmental friendly hydrophobic and superhydrophobic surfaces. The achieved hydrophobic membranes were very effective in the removal of VOCs (butanol, methyl-tert-butyl ether, and ethyl acetate) from binary aqueous solutions in vacuum membrane distillation. The correlation between membrane effectiveness and separated solvent polarity was compared in terms of material properties and resistance to the wetting (kinetics of wetting and in-depth liquid penetration). Material properties were interpreted considering Zisman theory and using Kao diagram. The significant influence of surface chemistry on the membrane performance was noticed (5 kDa, influence of hydrophobic nanolayer and separation controlled by solution-diffusion model; 300 kDa, no impact of surface chemistry and separation controlled by liquid-vapor equilibrium).

SYNTHESIS AND CHELATION PROPERTIES OF SOME NEW MANNICH CONDENSATION POLYMERS CONTAINING A SALICYLALDOXIME GROUP

ABSTRACT A new oxime containing polymer, Poly(salicylaldoxime-3,5-diyl (N,N′-dimethylethylenediamine N,N′-bismethylene)), polymer 1, was prepared through a Mannich-type condensation of salicylaldoxime with formaldehyde and N,N′-dimethylethylenediamine. Polymer 2, a crosslinked chelating ion exchange resin, was obtained by a similar Mannich condensation in presence of resorcinol as the crosslinker. The sorption properties of these polymers towards the divalent ions, Mg2+, Ca2+, Ni2+, Zn2+, Cd2+, and Cu2+ were studied by a batch equilibration technique as a function of contact time and pH. Crosslinking is found to have profound effects on the surface morphology and the chelation properties of these polymers. The crosslinked Polymer 2 exhibited improved chelation characteristics in comparison with Polymer 1 and displayed faster rates of metal ion uptake and relatively higher capacities and selectivities. These findings are in keeping with the observed increase in hydrophilic character upon crosslinking.

Soluble Peptidyl Phosphoranes for Metal-Free, Stereoselective Ligations in Organic and Aqueous Solution

Protocols for solid-phase syntheses of soluble peptidyl phosphoranes are presented. Various supported phosphoranylidene acetates were prepared on Rink amide or via alkylation of trialkyl- and triarylphosphines with bromoacetyl Wang ester. C-Acylation was conducted racemization-free with activated Fmoc-amino acids, followed by SPPS (solid-phase peptide synthesis). Acidic conditions released decarboxylated peptidyl phosphoranes into solution. The protocol allowed for the electronic variation of peptidyl phosphoranes which were investigated in ligation reactions with azides in organic and aqueous solvents.

Engineering of a highly efficient Xe₂*-excilamp (xenon excimer lamp, λmax=172 nm, η=40%) and qualitative comparison to a low-pressure mercury lamp (LP-Hg, λ=185/254 nm) for water purification.

Excilamps are mercury-free gas-discharge sources of non-coherent VUV or UV radiation with high radiant power and a long lifetime. The most efficient excilamp that is currently available on the market is a VUV xenon excilamp system (Xe2(*)-excimer lamp, λ(max) = 172 nm) with a stated radiant efficiency η of 40% at an electrical input power P(el) of 20 W, 50 W or 100 W. In this paper, the use of this highly efficient Xe2(*)-excilamp (P(el) = 20 W) for water treatment is demonstrated using a recirculating laboratory photoreactor system with negative radiation geometry. The efficiency in the 172 nm initiated bleaching of aqueous solutions of Rhodamine B is compared to that initiated by a common low-pressure mercury (LP-Hg) lamp (185 nm, TNN 15/32). The dependence of the pseudo zero order rate constant k´ of decolorization of RhB on the flow rate and on the initial concentration of RhB was investigated. Both lamps exhibited dependences of k´ on the initial concentration of RhB, which represents a typical saturation kinetical behavior. The saturation kinetics was very prominent in the case of the Xe2(*)-excilamp. Also, the Xe2(*)-excilamp treatment exhibited a significant influence on the flow rate of the RhB aqueous solution, which was not the case during the LP-Hg lamp initiated bleaching of RhB. The results of this paper demonstrate that Xe2(*)-excilamps can be used for VUV-initiated water purification. However, to reach the maximum efficacy of the Xe2(*)-excilamp for photo-initiated water purification further engineering optimization of the photoreactor concept is necessary.

Determination of Glucose Concentration in Aqueous Solution Using ATR-WT-IR Technique

Fourier transformation infrared (FT-IR) spectroscopy has been used to measure glucose concentrations in different matrices. The accuracy of the FT-IR technique does not meet the requirements of medical applications, so we have developed a new, efficient and precise method based on attenuated total reflectance coupled with wavelet transformation (ATR-WT-IR). One thousand interferograms, divided into training- and testing-sets, have been recorded from four glucose concentrations using an ATR-IR unit. Signals were subjected to (WT) and neural network (NN) study in order to design correlation algorithm. The Pearson’s Correlation Coefficient (PCC) obtained by judging the predicted- against the real-concentrations was 0.9954, with a mean square error of 8.4e-005. The proposed ATR-WT-IR method shows efficiency in glucose prediction and could possibly to be integrated into a non-invasive monitoring technique.

Olive mills wastewater treatment using local natural Jordanian clay

AbstractIn the Mediterranean area, olives are harvested and sent to mills where olive oil is extracted. These mills produce two types of wastes, namely olive kernel and olive mills wastewater (OMW). This OMW is considered an environmental problem because of its high organic content (COD over 80–200 g/l), high phenolics content (more than 400 mg/l), and low acidic pH (3–6). This study is about investigating the feasibility of using simple naturally occurring local Jordanian clay as a possible adsorbent to decrease the levels of the above negative characteristics of raw OMW as a step in developing a methodology to solve OMW problem without creating new problems to freshwater supply resources. Natural clay was calcined at several temperatures (350–550°C), some of which were further subjected to acid treatment using 1, 3, and 5 M-HCl solutions at 85°C. These treated clays were contacted with OMW in batch experiments to decide on optimum conditions to be used for a continuous packed bed treatment system. COD a...

Flexible, polymer-supported synthesis of sphingosine derivatives provides ceramides with enhanced biological activity

A polymer-supported route for the synthesis of sphingosine derivatives is presented based on the C-acylation of polymeric phosphoranylidene acetates with an Fmoc-protected amino acid. The approach enables the flexible variation of the sphingosine tail through a deprotection-decarboxylation sequence followed by E-selective Wittig olefination cleavage. d-Erythro-sphingosine analogs have been synthesized by diastereoselective reduction of the keto group employing LiAlH(O-tBu)3 as reducing agent. The effect of ceramides and keto-ceramides on the proliferation of three cancer cell lines HEP G-2, PC-12 and HL-60 was investigated and a ceramide containing an aromatic sphingosine tail was identified as being most active.

Advanced Material-Ordered Nanotubular Ceramic Membranes Covalently Capped with Single-Wall Carbon Nanotubes

Advanced ceramic materials with a well-defined nano-architecture of their surfaces were formed by applying a two-step procedure. Firstly, a primary amine was docked on the ordered nanotubular ceramic surface via a silanization process. Subsequently, single-wall carbon nanotubes (SWCNTs) were covalently grafted onto the surface via an amide building block. Physicochemical (e.g., hydrophobicity, and surface free energy (SFE)), mechanical, and tribological properties of the developed membranes were improved significantly. The design, preparation, and extended characterization of the developed membranes are presented. Tools such as high-resolution transmission electron microscopy (HR-TEM), single-area electron diffraction (SAED) analysis, microscopy, tribology, nano-indentation, and Raman spectroscopy, among other techniques, were utilized in the characterization of the developed membranes. As an effect of hydrophobization, the contact angles (CAs) changed from 38° to 110° and from 51° to 95° for the silanization of ceramic membranes 20 (CM20) and CM100, respectively. SWCNT functionalization reduced the CAs to 72° and 66° for ceramic membranes carbon nanotubes 20 (CM-CNT-20) and CM-CNT-100, respectively. The mechanical properties of the developed membranes improved significantly. From the nanotribological study, Young’s modulus increased from 3 to 39 GPa for CM-CNT-20 and from 43 to 48 GPa for pristine CM-CNT-100. Furthermore, the nanohardness increased by about 80% after the attachment of CNTs for both types of ceramics. The proposed protocol within this work for the development of functionalized ceramic membranes is both simple and efficient.