Reactivity of [(PNP)Mn(CO) 2 ] with Organophosphates
Not Available
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Engineering topics
Schmidt, Jurgen G.
Publications and source records attributed to Schmidt, Jurgen G..
Methods and systems for J-coupled nuclear magnetic resonance
A nuclear magnetic resonance (NMR) system is configured to detect combinatorial signatures stemming from homonuclear and heteronuclear J-couplings. The system comprises a pre-polarization system, a detector, and NMR electronics, wherein the detector includes an NMR magnet with a magnetic field of strength between 300 mT and 10 μT.
Williams, Robert F.↗
Label-free affinity screening, design and synthesis of inhibitors targeting the Mycobacterium tuberculosis L-alanine dehydrogenase
The ability of Mycobacterium tuberculosis (Mtb) to persist in its host may enable an evolutionary advantage for drug resistant variants to emerge. A potential strategy to prevent persistence and gain drug efficacy is to directly target the activity of enzymes that are crucial for persistence. We present a method for expedited discovery and structure-based design of lead compounds by targeting the hypoxia-associated enzyme L-alanine dehydrogenase (AlaDH). Biochemical and structural analyses of AlaDH confirmed binding of nucleoside derivatives and showed a site adjacent to the nucleoside binding pocket that can confer specificity to putative inhibitors. Using a combination of dye-ligand affinity chromatography, enzyme kinetics and protein crystallographic studies, we show the development and validation of drug prototypes. Crystal structures of AlaDH-inhibitor complexes with variations at the N6 position of the adenyl-moiety of the inhibitor provide insight into the molecular basis for the specificity of these compounds. We describe a drug-designing pipeline that aims to block Mtb to proliferate upon re-oxygenation by specifically blocking NAD accessibility to AlaDH. The collective approach to drug discovery was further evaluated through in silico analyses providing additional insight into an efficient drug development strategy that can be further assessed with the incorporation of in vivo studies.
60 APPLIED LIFE SCIENCES↗
PCP consensus protein/peptide alphavirus antigens stimulate broad spectrum neutralizing antibodies
Vaccines based on proteins and peptides may be safer and if calculated based on many sequences, more broad-spectrum than those designed based on single strains. Physicochemical Property Consensus (PCP con ) alphavirus (AV) antigens from the B-domain of the E2 envelope protein were designed, synthesized recombinantly and shown to be immunogenic (i.e. sera after inoculation detected the antigen in dotspots and ELISA). Antibodies in sera after inoculation with B-region antigens based on individual AV species (eastern or Venezuelan equine encephalitis (EEEV con , VEEV con ), or chikungunya (CHIKV con ) bound only their cognate protein, while those designed against multiple species (Mosaik con and EVC con ) recognized all three serotype specific antigens. The VEEV con and EEEV con sera only showed antiviral activity against their related strains (in plaque reduction neutralization assays (PRNT 50/80 ). Peptides designed to surface exposed areas of the E2-A-domain of CHIKV con were added to CHIKV con inocula to provide anti-CHIKV antibodies. EVC con , based on three different alphavirus species, combined with E2-A-domain peptides from AllAV con , a PCPcon of 24 diverse AV, generated broad spectrum, antiviral antibodies against VEEV, EEEV and CHIKV, AV with less than 35% amino acid identity to each other (>65% diversity). This is a promising start to a molecularly defined vaccine against all AV. A further study with these antigens can illuminate what areas are most important for a robust immune response, resistant to mutations in rapidly evolving viruses. The validated computational methods can also be used to design broad spectrum antigens against many other pathogen families.
59 BASIC BIOLOGICAL SCIENCES↗
Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (M pro also known as 3CL pro ) is a primary drug target, due to its essential role in maturation of the viral polyproteins. In this study, we provide crystallographic evidence, along with some binding assay data, that three clinically approved anti hepatitis C virus drugs and two other drug-like compounds covalently bind to the M pro Cys145 catalytic residue in the active site. Also, molecular docking studies can provide additional insight for the design of new antiviral inhibitors for SARS-CoV-2 using these drugs as lead compounds. One might consider derivatives of these lead compounds with higher affinity to the M pro as potential COVID-19 therapeutics for further testing and possibly clinical trials.
36 MATERIALS SCIENCE↗
Methods and systems for low to ultra-low magnetic field nuclear magnetic resonance for detecting chemical nerve agents
A nuclear magnetic resonance (NMR) system is configured to detect chemical threat material. The system comprises a magnet configured to generate a magnetic field of about 300 millitesla or less; and a probe configured to detect nuclear relaxation of at least two nuclei selected from the group consisting of 1H, 19F, 31P and 14N, and detect the spin density of nuclei selected from the group consisting of 1H, 19F, 31P and 14N, following excitation.
Williams, Robert F.↗
High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor
Not Available
60 APPLIED LIFE SCIENCES↗
Conformational control via sequence for a heteropeptoid in water: coupled NMR and Rosetta modelling
Structured water-soluble and hetero-oligomeric peptoids: the importance of peptoid-specific backbone restrictions.
Rajale, Trideep↗
Controlled cyclization of peptoids to form chiral diketopiperazines
The present disclosure provides improved methods for controlled cyclization of peptoid dimers to form N,N′-2,5-diketopiperazines (N,N′-2,5-DKPs) with significant selectivity. In at least some examples, selectivity is based on a serendipitous conglomeration of slow exchange of amide rotamers, steric repulsion from the degree of α-substitution, and the geometric bulk of an amine nucleophile. By varying reaction conditions, the selectivity of the reaction and formation of a particular N,N′-2,5-DKP can be switched. The cyclization works in the presence of a variety of protection groups and diverse functionalities. The teachings herein provide techniques for synthesizing N,N′-2,5-DKPs that can be readily docked with drug candidates for shuttling across the blood brain barrier. This method provides a facile way to produce substituted DKPs containing groups ready for post-modification to include docking drug candidates.
Williams, Robert F.↗
Engineering Catalysts for Selective Ester Hydrogenation
The development of efficient catalysts and processes for synthesizing functionalized (olefinic and/or chiral) primary alcohols and fluoral hemiacetals is currently needed. These are valuable building blocks for pharmaceuticals, agrochemicals, perfumes, and so forth. From an economic standpoint, bench-stable Takasago Int. Corp.’s Ru-PNP, more commonly known as Ru-MACHO, and Gusev’s Ru-SNS complexes are arguably the most appealing molecular catalysts to access primary alcohols from esters and H 2 . This work introduces economically competitive Ru-SNP(O) z complexes ( z = 0, 1), which combine key structural elements of both of these catalysts. In particular, the incorporation of SNP heteroatoms into the ligand skeleton was found to be crucial for the design of a more product-selective catalyst in the synthesis of fluoral hemiacetals under kinetically controlled conditions. Based on experimental observations and computational analysis, this paper further extends the current state-of-the-art understanding of the accelerative role of KO- t -C 4 H 9 in ester hydrogenation. Finally, it attempts to explain why a maximum turnover is seen to occur starting at ~25 mol % base, in contrast to only ~10 mol % with ketones as substrates.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Enantiomeric Cross-Inhibition in the Synthesis of Oligonucleotides on a Nonchiral Template
Prebiotic syntheses of chiral monomers always yield racemic mixtures. Living systems, however, utilize L-amino acids and D-nucleotides in their biopolymers. The generation of optical asymmetry by selection and amplification in an autocatalytic process is, therefore, an important element in many theories of the origin of life. Replication of polynucleotides in template-directed syntheses is an obvious candidate for such an amplification step in a pre-'RNA world'. A serious objection to this suggestion is the observation that the efficiency of template-directed syntheses of RNA is limited by enantiomeric cross-inhibition. Peptide Nucleic Acids (PNAs), amide-linked, nonchiral analogues of RNA, have been 'copied' into RNA and constitute an alternative to chiral polynucleotides as an informational replicating system. Here, we use PNA as model for a hypothetical, nonchiral precursor of RNA in experiments re-examining enantiomeric cross-inhibition. We find that enantiomeric cross-inhibition is as serious in the polymerization of nucleotides on a PNA template as it is on a conventional RNA or DNA template.
Schmidt, Jurgen G.↗
Separation of 'Uncharged' Oligodeoxynucleotide Analogs by Anion-Exchange Chromatography at High pH
Ion-exchange chromatography is a well-established method for the analysis and purification of phosphodiester-linked oligonucleotides. If elution is carried out under alkaline conditions, the secondary structure of G- and C-rich oligomers is disrupted. Furthermore, elution times become more sensitive to the G and T content of the oligomer, because G and T are deprotonated at pH 10. In recent work on peptide-nucleic acids (PNAs) we noted that mixtures of PNA oligomers G(sub 4), G(sub 6), G(sub 8), and G9(sub 10) are readily separated by elution at pH 12 on an RPC-5 column. Here we show that this separation method is more generally applicable.
Schmidt, Jurgen G.↗
Separation of Uncharged Oligodeoxynucleotide Analogs by Anion-Exchange Chromatography at High pH
Ion-exchange chromatography is a well-established method for the analysis and purification of phosphodiester-linked oligonucleotides. If elution is carried out under alkaline conditions, the secondary structure of G- and C-rich oligomers is disrupted. Furthermore, elution times become more sensitive to the G and T content of the oligomer, because G and T are deprotonated at pH 10. In recent work on peptide-nucleic acids (PNAs) we noted that mixtures of PNA oligomers G(sub 4), G(Sub 6), G(sub 8), and G(sub 10) are readily separated by elution at pH 12 on an RPC-5 column. Here we show that this separation method is more generally applicable.
Schmidt, Jurgen G.↗