scholarly journals Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5228
Author(s):  
Samo Guzelj ◽  
Žiga Jakopin
Keyword(s):  
Chemical Space ◽  
Structural Features ◽  
Innate Immune ◽  
Diaminopimelic Acid ◽  
Side Chain ◽  
Structural Fragment ◽  
Amino Group ◽  
Conformationally Constrained ◽  
Structural Modifications ◽  
Agonistic Activity

The dipeptide d-Glu-meso-DAP (iE-DAP) is the minimal structural fragment capable of activating the innate immune receptor nucleotide-binding oligomerization domain protein (NOD1). The meso-diaminopimelic acid (meso-DAP) moiety is known to be very stringent in terms of the allowed structural modifications which still retain the NOD1 activity. The aim of our study was to further explore the chemical space around the meso-DAP portion and provide a deeper understanding of the structural features required for NOD1 agonism. In order to achieve the rigidization of the terminal amine functionality of meso-DAP, isoxazoline and pyridine heterocycles were introduced into its side-chain. Further, we incorporated the obtained meso-DAP mimetics into the structure of iE-DAP. Collectively, nine innovative iE-DAP derivatives additionally equipped with lauroyl or didodecyl moieties at the α-amino group of d-Glu have been prepared and examined for their NOD1 activating capacity. Overall, the results obtained indicate that constraining the terminal amino group of meso-DAP abrogates the compounds’ ability to activate NOD1, since only compound 6b retained noteworthy NOD1 agonistic activity, and underpin the stringent nature of this amino acid with regard to the allowed structural modifications.

scholarly journals Sortase C-Mediated Anchoring of BasI to the Cell Wall Envelope of Bacillus anthracis

2007 ◽  
Vol 189 (17) ◽  
pp. 6425-6436 ◽  
Author(s):  
Luciano A. Marraffini ◽  
Olaf Schneewind
Keyword(s):  
Cell Wall ◽  
Bacillus Anthracis ◽  
Active Site ◽  
Diaminopimelic Acid ◽  
Side Chain ◽  
Carboxyl Group ◽  
Amino Group ◽  
Active Site Cysteine ◽  
New Hosts ◽  
Host Death

ABSTRACT Vegetative forms of Bacillus anthracis replicate in tissues of an infected host and precipitate lethal anthrax disease. Upon host death, bacilli form dormant spores that contaminate the environment, thereby gaining entry into new hosts where spores germinate and once again replicate as vegetative forms. We show here that sortase C, an enzyme that is required for the formation of infectious spores, anchors BasI polypeptide to the envelope of predivisional sporulating bacilli. BasI anchoring to the cell wall requires the active site cysteine of sortase C and an LPNTA motif sorting signal at the C-terminal end of the BasI precursor. The LPNTA motif of BasI is cleaved between the threonine (T) and the alanine (A) residue; the C-terminal carboxyl group of threonine is subsequently amide linked to the side chain amino group of diaminopimelic acid within the wall peptides of B. anthracis peptidoglycan.

scholarly journals Chalcones: Synthetic Chemistry Follows Where Nature Leads

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1203
Author(s):  
Hiba A. Jasim ◽  
Lutfun Nahar ◽  
Mohammad A. Jasim ◽  
Sharon A. Moore ◽  
Kenneth J. Ritchie ◽  
...  
Keyword(s):  
Critical Appraisal ◽  
Chemical Space ◽  
Structural Features ◽  
Structural Modifications ◽  
Chalcone Derivatives ◽  
Bioactive Natural Products ◽  
Bioinspired Synthesis ◽  
Naturally Occurring ◽  
Reduced Toxicity ◽  
Unique Chemical

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action.

scholarly journals Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme

2021 ◽  
Vol 22 (3) ◽  
pp. 1496
Author(s):  
Domenico Loreto ◽  
Giarita Ferraro ◽  
Antonello Merlino
Keyword(s):  
Anticancer Agents ◽  
Structural Features ◽  
Side Chain ◽  
Side Chains ◽  
Valuable Insight ◽  
Experimental Conditions ◽  
Egg White Lysozyme ◽  
Potential Applications ◽  
Model Protein ◽  
Hen Egg White

The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh2(μ-O2CCH3)4] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh2(μ-O2CCH3)4] extensively reacts with HEWL:it in part breaks down, at variance with what happens in reactions with other proteins. A Rh center coordinates the side chains of Arg14 and His15. Dimeric Rh–Rh units with Rh–Rh distances between 2.3 and 2.5 Å are bound to the side chains of Asp18, Asp101, Asn93, and Lys96, while a dirhodium unit with a Rh–Rh distance of 3.2–3.4 Å binds the C-terminal carboxylate and the side chain of Lys13 at the interface between two symmetry-related molecules. An additional monometallic fragment binds the side chain of Lys33. These data, which are supported by replicated structural determinations, shed light on the reactivity of dirhodium tetracarboxylates with proteins, providing useful information for the design of new Rh-containing biomaterials with an array of potential applications in the field of catalysis or of medicinal chemistry and valuable insight into the mechanism of action of these potential anticancer agents.

scholarly journals Small and Simple, yet Sturdy: Conformationally Constrained Peptides with Remarkable Properties

2021 ◽  
Vol 22 (4) ◽  
pp. 1611
Author(s):  
Krištof Bozovičar ◽  
Tomaž Bratkovič
Keyword(s):  
Chemical Space ◽  
Structure Optimization ◽  
Peptide Chain ◽  
Conformationally Constrained ◽  
Drug Candidates ◽  
Conformational Constraints ◽  
Macrocyclic Peptides ◽  
Constrained Peptides ◽  
Sheer Size

The sheer size and vast chemical space (i.e., diverse repertoire and spatial distribution of functional groups) underlie peptides’ ability to engage in specific interactions with targets of various structures. However, the inherent flexibility of the peptide chain negatively affects binding affinity and metabolic stability, thereby severely limiting the use of peptides as medicines. Imposing conformational constraints to the peptide chain offers to solve these problems but typically requires laborious structure optimization. Alternatively, libraries of constrained peptides with randomized modules can be screened for specific functions. Here, we present the properties of conformationally constrained peptides and review rigidification chemistries/strategies, as well as synthetic and enzymatic methods of producing macrocyclic peptides. Furthermore, we discuss the in vitro molecular evolution methods for the development of constrained peptides with pre-defined functions. Finally, we briefly present applications of selected constrained peptides to illustrate their exceptional properties as drug candidates, molecular recognition probes, and minimalist catalysts.

scholarly journals Structure-Activity Relationships of Sandalwood Odorants: Synthesis of a New Campholene Derivative

2010 ◽  
Vol 5 (9) ◽  
pp. 1934578X1000500
Author(s):  
Iris Stappen ◽  
Joris Höfinghoff ◽  
Gerhard Buchbauer ◽  
Peter Wolschann
Keyword(s):  
Structural Changes ◽  
Great Influence ◽  
Complete Loss ◽  
Side Chain ◽  
Side Chains ◽  
Quaternary Carbon ◽  
Structural Modifications ◽  
Structure Activity ◽  
Highly Sensitive ◽  
Sandalwood Odorants

Structural modifications of natural (-)-( Z)-β-santalol have shown that the sandalwood odor impression is highly sensitive, even to small structural changes. Particularly, the substitution of the quaternary carbon is of great influence on the scent. Epi-compounds with side chains in the endo-position possess sandalwood odor in only a few derivatives, whereas modifications at this side chain, as well as modification at the bicyclic ring systems mostly lead to a complete loss of sandalwood fragrance.

Synthesis of characteristic Mycobacterium peptidoglycan (PGN) fragments utilizing with chemoenzymatic preparation of meso-diaminopimelic acid (DAP), and their modulation of innate immune responses

2016 ◽  
Vol 14 (3) ◽  
pp. 1013-1023 ◽  
Author(s):  
Qianqian Wang ◽  
Yusuke Matsuo ◽  
Ambara R. Pradipta ◽  
Naohiro Inohara ◽  
Yukari Fujimoto ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Diaminopimelic Acid ◽  
Innate Immune Responses

CharacteristicMycobacteriumpeptidoglycan fragments were comprehensively synthesized and their weaker immunostimulationviaNod1 and Nod2 was shown.

Tanshinone IIA: Pharmacology, total synthesis, and progress in structure-modifications

2021 ◽  
Vol 28 ◽  
Author(s):  
Xing Huang ◽  
Hao Deng ◽  
Qing-kun Shen ◽  
Zhe-Shan Quan
Keyword(s):  
Herbal Medicine ◽  
Total Synthesis ◽  
Chinese Herbal Medicine ◽  
Biological Activities ◽  
Structural Features ◽  
Tanshinone Iia ◽  
Structural Modifications ◽  
Chinese Herbal ◽  
Bioactive Constituent

: Tanshinone IIA, a major bioactive constituent of Danshen, a Chinese herbal medicine, has gained extensive exploration owing to its unique structural features and multiple promising biological activities. This review focuses on the pharmacology, total synthesis, and structural modifications of tanshinone IIA. We hope this review will contribute to a better understanding of the progress in the field and provide constructive suggestions for further study of tanshinone IIA.

Salt bridges in model peptides

1988 ◽  
Vol 53 (11) ◽  
pp. 2810-2824 ◽  
Author(s):  
Ilmars Sekacis ◽  
Mark Shenderovich ◽  
Gregory Nikiforovich ◽  
Edvards Liepinš ◽  
Ludmila Polevaya ◽  
...  
Keyword(s):  
Synthetic Peptides ◽  
Salt Bridge ◽  
Peptide Bond ◽  
Space Structure ◽  
Side Chain ◽  
Amino Group ◽  
Salt Bridges ◽  
Ionic Bond ◽  
Theoretical Conformational Analysis ◽  
H Nmr

A group of synthetic peptides including Boc-Lys-Phe-X-Y, X = Ala (I, III) or Thr (II), Y = Pro (I, II) or Ala (III) was studied by means of 1H NMR spectroscopy and theoretical conformational analysis. Compound I in DMSO shows two conformers with the trans- and cis-configuration of the peptide bond Ala-Pro. The salt bridge between the Lys ε-amino group and the C-terminal carboxyl is featured by magnetic nonequivalence of the Lys CεH2 protons. The space structure of I and II was found to possess a salt bridge fixed by an unusual turn in the chain formed by the Lys side chain and the C-terminal dipeptide with the trans-peptide bond X-Pro. Since a stable ionic bond in III and in the cis-conformer of I has not been observed, its contribution to stabilization of the space structure of the peptides in DMSO appears rather small.

scholarly journals Re-profiling of natural inhibitor via combinatorial drug screening: Brefeldin A variant design as an effective antagonist leading to EPAC2 structure modification and antibody design for identification

2021 ◽  
Author(s):  
Akshay Uttarkar ◽  
Vidya Niranjan
Keyword(s):  
Tertiary Structure ◽  
Chemical Space ◽  
Brefeldin A ◽  
Side Chain ◽  
Simulation Studies ◽  
Structure Modification ◽  
Single Domain Antibody ◽  
Domain Antibody ◽  
Natural Inhibitor ◽  
Antibody Design

Drug discovery can be impactful with re-purposing and combinatorial strategies leading to potential pharmaceutical outputs. Epac2 has been a target of interest for various physiological conditions where suppression is inevitable to achieve desired therapeutic effect. Epac isoforms inhibition is crucial in vascular functions to prevent chronic inflammation leading to hypertension and myocardial infarction. An attempt utilizing brefeldin A, a natural inhibitor was sub-jected to substitution of 3 side chain groups with 43 fragments via combinatorial strategy. This resulted in generating a library of 79507 brefeldin A variants. High throughput virtual screening yielded 68,043 variants followed by precision docking providing 117 lead like brefeldin A vari-ants. The best docked variant (3-((1R,2E,6R,10E,11aS,13S,14A)-6-(methylsulfonamido)-13-(3-methylureido)-4-oxo-4,6,7,8,9,11a,12,13,14,14a-decahydro-1H-cyclopenta[f][1]oxacyclotridecin-1-yl)-2,3-dihydro-1Himidazol-1-ium) has an increased binding efficiency of -10.841 kcal/mol. Simulation studies up to 200ns of complex lead to re-orientation of target tertiary structure resulted in RMSD change of 30.221 angstrom, suggesting the epac2 structure modification leading to unavailability of RAS-GEF domain and its interaction with Rap1b. A single domain antibody was designed to bind specifically to re-structured epac2 for potential identification over the native target structure. The resulting Brefeldin variant can be potentially labelled as a most effective antagonist against epac2 which induces theoretically irreversible structural re-conformation. This study also provides a robust in-silico workflow for searching of chemical space, generating and screening of combination libraries and the efficient utilization of known inhibitor.

Synthesis and Studies on the Effect of Phenyl Side – Chain Content on Refractive Index of Polysiloxane Resin

2015 ◽  
Vol 754-755 ◽  
pp. 881-885
Author(s):  
Rafiza Ramli ◽  
Ng Chee Mang ◽  
Zulkifli Ahmad ◽  
Mariatti Jaafar ◽  
Mohd Remy Rozainy Mohd Arif Zainol
Keyword(s):  
Refractive Index ◽  
High Refractive Index ◽  
Linear Increase ◽  
Solution Viscosity ◽  
Side Chain ◽  
High Brightness ◽  
Structural Modifications ◽  
H Nmr ◽  
Siloxane Oligomers ◽  
Uv Visible

A series of high refractive index of α,ω-vinyl silyl terminated polydimethylsiloxane-co-polydiphenylsiloxane was synthesized by the equilibration ring opening – anionic polymerization of cyclic organo-siloxane oligomers in the present of 1,3-divinyltetramethyldisiloxane as terminating agent. Structural modifications were characterized by use of FTIR, H-NMR, and solution viscosity. UV-visible spectroscopy was analyzed which reveal a good transmittance in the region 400 – 750 nm radiation for all polysiloxanes.The presence of diphenylsiloxane unit results in a linear increase of the refractive index of the resin. These features favor good application as encapsulant for high brightness LED (HBLED) packaging.

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