scholarly journals Inhibitors of inosine 5′-monophosphate dehydrogenase as emerging new generation antimicrobial agents

MedChemComm ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 1290-1301 ◽  
Author(s):  
Kapil Juvale ◽  
Althaf Shaik ◽  
Sivapriya Kirubakaran
Keyword(s):  
Antimicrobial Agents ◽  
De Novo ◽  
Guanine Nucleotides ◽  
New Generation ◽  
Monophosphate Dehydrogenase

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a vital enzyme involved in thede novosynthesis of guanine nucleotides. Inhibitors of bacterial IMPDH hold great potential as new generation antimicrobial agents.

scholarly journals Targeted Disruption of the Inosine 5′-Monophosphate Dehydrogenase Type I Gene in Mice

2003 ◽  
Vol 23 (18) ◽  
pp. 6702-6712 ◽  
Author(s):  
Jing Jin Gu ◽  
Amy K. Tolin ◽  
Jugnu Jain ◽  
Hai Huang ◽  
Lalaine Santiago ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Cytolytic Activity ◽  
Guanine Nucleotides ◽  
Interleukin 4 ◽  
Type I ◽  
Double Knockout ◽  
Inhibition Of Proliferation ◽  
Monophosphate Dehydrogenase

ABSTRACT Inosine 5′-monophosphate dehydrogenase (IMPDH) is the critical, rate-limiting enzyme in the de novo biosynthesis pathway for guanine nucleotides. Two separate isoenzymes, designated IMPDH types I and II, contribute to IMPDH activity. An additional pathway salvages guanine through the activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) to supply the cell with guanine nucleotides. In order to better understand the relative contributions of IMPDH types I and II and HPRT to normal biological function, a mouse deficient in IMPDH type I was generated by standard gene-targeting techniques and bred to mice deficient in HPRT or heterozygous for IMPDH type II. T-cell activation in response to anti-CD3 plus anti-CD28 antibodies was significantly impaired in both single- and double-knockout mice, whereas a more general inhibition of proliferation in response to other T- and B-cell mitogens was observed only in mice deficient in both enzymes. In addition, IMPDH type I−/− HPRT−/0 splenocytes showed reduced interleukin-4 production and impaired cytolytic activity after antibody activation, indicating an important role for guanine salvage in supplementing the de novo synthesis of guanine nucleotides. We conclude that both IMPDH and HPRT activities contribute to normal T-lymphocyte activation and function.

scholarly journals LeafGo: Leaf to Genome, a quick workflow to produce high-quality De novo genomes with Third Generation Sequencing technology

2021 ◽  
Author(s):  
Patrick Driguez ◽  
Salim Bougouffa ◽  
Karen Carty ◽  
Alexander Putra ◽  
Kamel Jabbari ◽  
...  
Keyword(s):  
De Novo ◽  
Rapid Development ◽  
Plant Genome ◽  
Plant Genomics ◽  
High Quality ◽  
High Molecular Weight Dna ◽  
Tissue Samples ◽  
Sequencing Technologies ◽  
The Cost ◽  
New Generation

AbstractRecent years have witnessed a rapid development of sequencing technologies. Fundamental differences and limitations among various platforms impact the time, the cost and the accuracy for sequencing whole genomes. Here we designed a complete de novo plant genome generation workflow that starts from plant tissue samples and produces high-quality draft genomes with relatively modest laboratory and bioinformatic resources within seven days. To optimize our workflow we selected different species of plants which were used to extract high molecular weight DNA, to make PacBio and ONT libraries for sequencing with the Sequel I, Sequel II and GridION platforms. We assembled high-quality draft genomes of two different Eucalyptus species E. rudis, and E. camaldulensis to chromosome level without using additional scaffolding technologies. For the rapid production of de novo genome assembly of plant species we showed that our DNA extraction protocol followed by PacBio high fidelity sequencing, and assembly with new generation assemblers such as hifiasm produce excellent results. Our findings will be a valuable benchmark for groups planning wet- and dry-lab plant genomics research and for high throughput plant genomics initiatives.

scholarly journals Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
George Ueda ◽  
Aleksandar Antanasijevic ◽  
Jorge A Fallas ◽  
William Sheffler ◽  
Jeffrey Copps ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
De Novo ◽  
Viral Glycoprotein ◽  
Influenza Hemagglutinin ◽  
Self Assembling ◽  
Cryo Electron Microscopy ◽  
Viral Glycoproteins ◽  
Protein Nanoparticles ◽  
New Generation ◽  
Tailored Design

Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.

Long-term efficacy of drug coated balloons compared with new generation drug-eluting stents for the treatment of de novo coronary artery lesions

2018 ◽  
Vol 92 (5) ◽  
pp. E317-E326 ◽  
Author(s):  
Dimitrios Venetsanos ◽  
Sofia Sederholm Lawesson ◽  
Georgios Panayi ◽  
Tim Tödt ◽  
Ulf Berglund ◽  
...  
Keyword(s):  
Coronary Artery ◽  
De Novo ◽  
Drug Eluting Stents ◽  
Coronary Artery Lesions ◽  
Term Efficacy ◽  
Drug Eluting ◽  
New Generation

The new generation hDHODH inhibitor MEDS433 hinders the in vitro replication of SARS-CoV-2

2020 ◽  
Author(s):  
Arianna Calistri ◽  
Anna Luganini ◽  
Valeria Conciatori ◽  
Claudia Del Vecchio ◽  
Stefano Sainas ◽  
...  
Keyword(s):  
Virus Replication ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
In Vitro Replication ◽  
Attractive Candidate ◽  
New Generation ◽  
Effective Drugs ◽  
Nanomolar Range

AbstractIdentification and development of effective drugs active against SARS-CoV-2 are urgently needed. Here, we report on the anti-SARS-CoV-2 activity of MEDS433, a novel inhibitor of human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidines biosynthesis. MEDS433 inhibits in vitro virus replication in the low nanomolar range, and through a mechanism that stems from its ability to block hDHODH activity. MEDS433 thus represents an attractive candidate to develop novel anti-SARS-CoV-2 agents.

scholarly journals A Safe and Multitasking Antimicrobial Decapeptide: The Road from De Novo Design to Structural and Functional Characterization

2020 ◽  
Vol 21 (18) ◽  
pp. 6952
Author(s):  
Bruna Agrillo ◽  
Yolande T. R. Proroga ◽  
Marta Gogliettino ◽  
Marco Balestrieri ◽  
Rosarita Tatè ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Fungal Pathogens ◽  
Antimicrobial Agents ◽  
De Novo ◽  
Low Cost ◽  
Functional Characterization ◽  
Human Keratinocytes ◽  
Minimal Bactericidal Concentration ◽  
Microbial Spoilage ◽  
Structural Resistance

Antimicrobial peptides (AMPs) are excellent candidates to fight multi-resistant pathogens worldwide and are considered promising bio-preservatives to control microbial spoilage through food processing. To date, designing de novo AMPs with high therapeutic indexes, low-cost synthesis, high resistance, and bioavailability, remains a challenge. In this study, a novel decapeptide, named RiLK1, was rationally designed starting from the sequence of the previously characterized AMP 1018-K6, with the aim of developing short peptides, and promoting higher selectivity over mammalian cells, antibacterial activity, and structural resistance under different salt, pH, and temperature conditions. Interestingly, RiLK1 displayed a broad-spectrum of bactericidal activity against Gram-positive and Gram-negative bacteria, including multidrug resistant clinical isolates of Salmonella species, with Minimal Bactericidal Concentration (MBC) values in low micromolar range, and it was effective even against two fungal pathogens with no evidence of cytotoxicity on human keratinocytes and fibroblasts. Moreover, RiLK1-activated polypropylene films were revealed to efficiently prevent the growth of microbial spoilage, possibly improving the shelf life of fresh food products. These results suggested that de novo designed peptide RiLK1 could be the first candidate for the development of a promising class of decameric and multitask antimicrobial agents to overcome drug-resistance phenomena.

Clinical and angiographic performance of a new-generation modular stent design for treatment of de novo coronary lesions

2001 ◽  
Vol 54 (3) ◽  
pp. 276-282 ◽  
Author(s):  
Victor M. Legrand ◽  
Eulogio J. Garcia ◽  
Eberhard Grube ◽  
Khalife Khalife ◽  
Hans Bonnier ◽  
...  
Keyword(s):  
De Novo ◽  
Stent Design ◽  
Coronary Lesions ◽  
New Generation

scholarly journals β-Lytic Protease of Lysobacter capsici VKM B-2533T

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 744
Author(s):  
Alexey S. Afoshin ◽  
Mihail A. Konstantinov ◽  
Ilya Yu. Toropygin ◽  
Irina V. Kudryakova ◽  
Natalia V. Vasilyeva
Keyword(s):  
Antimicrobial Agents ◽  
Biochemical Characterization ◽  
Micrococcus Luteus ◽  
Culture Liquid ◽  
Living Cells ◽  
Peptide Bonds ◽  
Protein Substrates ◽  
Proteolytic Activities ◽  
Proteolytic Action ◽  
New Generation

Bacteriolytic enzymes are promising antimicrobial agents for developing new-generation drugs. Recently, we have isolated a β-lytic protease (BlpLc) from the culture liquid of Lysobacter capsici VKM B-2533T. This BlpLc possesses a valuable property, not described for β-lytic proteases (Blps) earlier, of hydrolyzing living cells of Staphylococcus aureus 55 MRSA clinical isolate. This work phylogenetically characterized the BlpLc and investigated its properties. Analysis revealed a variability of pre-/pro-parts of Blp precursors. The mature BlpLc is the closest to the earlier annotated but not isolated Blp from Lysobacter sp. Root690. The biochemical characterization found conditions for the BlpLc general bacteriolytic activity relative to autoclaved S. aureus 209P cells to differ from that of earlier isolated Blp. Unexpected was the effect of serine (phenylmethylsulfonyl fluoride (PMSF)) and cysteine (p-chloromercuribenzoate (p-CMB)) protease inhibitors on BlpLc bacteriolytic and proteolytic activities. The specificity of BlpLc proteolytic action relative to hemoglobin, elastin, gelatin, collagen, azofibrin, myoglobin, ovalbumin, and ovamucoid was found. New types of peptide bonds—Gly-X, Ser-X, Lys-X, Ala-X, Val-X, Glu-X, and Phe-X—hydrolyzed by the enzyme in protein substrates were first revealed using MALDI-TOF. Turbidimetrically, the BlpLc was found to lyze living cells of S. aureus 209P, Micrococcus luteus B1819, and M. roseus B1236, which is important for expanding the enzyme’s applied properties.

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