Amino Acid Residues In Peptides Research Articles

Identification of calcium chelating peptides from peanut protein hydrolysate and absorption activity of peptide-calcium complex.

Peanut peptides have good chelating ability with metal ions. However, there are few studies on the chelation mechanism of peanut peptides with calcium and absorption properties of peptide-calcium complex. Peptides with high calcium chelating rate were isolated and purified from peanut protein hydrolysate (PPH), and the chelation rate of component F21 was higher (81.4 ± 0.8%). Six peptides were identified from component F21 by liquid chromatography-tandem mass spectrometry, and the frequency of acidic amino acids and arginine in the amino acid sequence was higher in all six peptides. Peanut peptide-calcium complex (PPH21-Ca) was prepared by selecting component F21 (PPH21). Ultraviolet analysis indicated that the chelate reaction occurred between peanut peptide and calcium ions. Fourier transform infrared analysis showed that the chelating sites were carboxyl and amino groups on the amino acid residues of peptides. Scanning electron microscopy revealed that the surface of peanut peptide had a smooth block structure, but the surface of the complex had a granular morphology. Caco-2 cell model tests revealed that the bioavailability of PPH21-Ca was 58.4 ± 0.5%, which was significantly higher than that of inorganic calcium at 37.0 ± 0.4%. Peanut peptides can chelate calcium ions by carboxyl and amino groups, and the peptide-calcium complex had higher bioavailability. This study provides a theoretical basis for the development of new calcium supplement products that are absorbed easily. © 2024 Society of Chemical Industry.

РАЗРАБОТКА С ИСПОЛЬЗОВАНИЕМ МОЛЕКУЛЯРНОЙ ПЕПТИДНОЙ ТРАНСПЛАНТАЦИИ ПОТЕНЦИАЛЬНОГО НЕЙРОПРОТЕКТОРНОГО БИОПЕПТИДА

The present research is focused on design of new nutritional neuroprotective biopeptide, using method of molecular peptide transplantation (MPT) based on analysis of literature sources, databases on biophysical properties and biological activity of peptides. The objects of the research are sequences of amino acid residues of peptides with proven neuroprotective properties. Prediction of biological activity of the developed biopeptide was carried out using the Peptide Ranker database (http://distilldeep.ucd.ie/PeptideRanker). Information on cyclic peptides frameworks that are resistant to proteolysis was obtained in the Cybase database (http://www.cybase.org.au), biopeptide identification was carried out using the EROP-Moscow database (http://erop.inbi.ras.ru/index.html), biophysical properties assessment of the developed biopeptide was carried out using the PepCalc peptide properties calculator (http://pepcalc.com) and APD 3 databases (https://aps.unmc.edu/home). A neuro-protective interfering peptide has been developed by preliminary preparation of a cyclotide-based framework followed by insertion of short HFRWPGP peptide into the framework by the MPT method. The developed peptide has the following sequence of amino acid residues: PCRRRCHFRWPGPCRGRCP, has high biological activity equal to 0.89. The hydrophobicity of the peptide according to Wimley-White in the whole residue is 2.91, therefore, the peptide is well soluble in water. The protein binding potential (Boman index) is high and is 4.3 kcal / mol, indicating its ability to bind to target receptors.

Electrochemistry-enabled residue-specific modification of peptides and proteins.

Selective chemical reactions at precise amino acid residues of peptides and proteins have become an exploding field of research in the last few decades. With the emerging utility of bioconjugated peptides and proteins as drug leads and therapeutic agents, the design of smart protocols to modulate and conjugate biomolecules has become necessary. During this modification, the most important concern of biochemists is to keep intact the structural integrity of the biomolecules. Hence, a soft and selective biocompatible reaction environment is necessary. Electrochemistry, a mild and elegant tunable reaction platform to synthesize complex molecules while avoiding harsh and toxic chemicals, can provide such a reaction condition. However, this strategy is yet to be fully exploited in the field of selective modification of polypeptides. With this possibility, the use of electrochemistry as a reaction toolbox in peptide and protein chemistry is flourishing day by day. Unfortunately, there is no suitable review article summarizing the residue-specific modification of biomolecules. The present review provides a comprehensive summary of the latest manifested electrochemical approaches for the modulation of five redox-active amino acid residues, namely cysteine, tyrosine, tryptophan, histidine and methionine, found in peptides and proteins. The article also highlights the incredible potential of electrochemistry for the regio- as well as chemoselective bioconjugation strategy of biomolecules.

Introduction of a fatty acid chain modification to prolong circulatory half-life of a radioligand towards glucose-dependent insulinotropic polypeptide receptor

BackgroundThe beneficial role of glucose-dependent insulinotropic polypeptide receptor (GIPR) in weight control and maintaining glucose levels has led to the development of several multi-agonistic peptide drug candidates, targeting GIPR and glucagon like peptide 1 receptor (GLP1R) and/or the glucagon receptor (GCGR). The in vivo quantification of target occupancy by these drugs would accelerate the development of new drug candidates. The aim of this study was to evaluate a novel peptide (GIP1234), based on previously reported ligand DOTA-GIP-C803, modified with a fatty acid moiety to prolong its blood circulation. It would allow higher target tissue exposure and consequently improved peptide uptake as well as in vivo PET imaging and quantification of GIPR occupancy by novel drugs of interest. MethodA 40 amino acid residue peptide (GIP1234) was synthesized based on DOTA-GIP-C803, in turn based on the sequences of endogenous GIP and Exendin-4 with specific amino acid modifications to obtain GIPR selectivity. A palmitoyl fatty acid chain was furthermore added at Lys14 via a glutamic acid linker to prolong its blood circulation time by the interaction with albumin. GIP1234 was conjugated with a DOTA chelator at the C-terminal cysteine residue to achieve 68Ga radiolabeling. The resulting PET probe, [68Ga]Ga-DOTA-GIP1234 was evaluated for receptor binding specificity and selectivity using HEK293 cells transfected with human GIPR, GLP1R, or GCGR. Blocking experiments with tirzepatide (2 μM) were conducted using huGIPR HEK293 cells to investigate binding specificity. Ex vivo and in vivo organ distribution of [68Ga]Ga-DOTA-GIP1234 was studied in rats and a pig in comparison to [68Ga]Ga-DOTA-C803-GIP. Binding of [68Ga]Ga-DOTA-GIP1234 to albumin was assessed in situ using polyacrylamide gel electrophoresis (PAGE). The stability was tested in formulation buffer and rat blood plasma. Results[68Ga]Ga-DOTA-GIP1234 was synthesized with non-decay corrected radiochemical yield of 88 ± 3.7 % and radiochemical purity of 97.8 ± 0.8 %. The molar activity for the radiotracer was 8.1 ± 1.1 MBq/nmol. [68Ga]Ga-DOTA-GIP1234 was stable and maintained affinity to huGIPR HEK293 cells (dissociation constant (Kd) = 40 ± 12.5 nM). The binding of [68Ga]Ga-DOTA-GIP1234 to huGCGR and huGLP1R cells was insignificant. Pre-incubation of huGIPR HEK293 cell sections with tirzepatide resulted in the decrease of [68Ga]Ga-DOTA-GIP1234 binding by close to 90 %. [68Ga]Ga-DOTA-GIP1234 displayed slow blood clearance in pigs with SUV = 3.5 after 60 min. Blood retention of the tracer in rat was 2-fold higher than that of [68Ga]Ga-DOTA-C803-GIP. [68Ga]Ga-DOTA-GIP1234 also demonstrated strong liver uptake in both pig and rat combined with decreased renal excretion. The concentration dependent binding of [68Ga]Ga-DOTA-GIP1234 to albumin was confirmed in situ by PAGE. Conclusion[68Ga]Ga-DOTA-GIP1234 demonstrated nanomolar affinity and selectivity for huGIPR in vitro. Addition of a fatty acid moiety prolonged blood circulation time and tissue exposure in both rat and pig in vivo. However, the liver uptake was also increased which may make PET imaging of abdominal tissues such as pancreas challenging. The investigation of the influence of fatty acid moiety on the biological performance of the peptide ligand paved the way for further rational design of GIPR ligand analogues with improved characteristics.

Antibacterial and anticancer activity of two NK-lysin-derived peptides from the Antarctic teleost Trematomus bernacchii

The NK-lysin antimicrobial peptide, first identified in mammals, possesses both antibacterial and cytotoxic activity against cancer cell lines. Homologue peptides isolated from different fish species have been examined for their functional characteristics in the last few years. In this study, a NK-lysin transcript was identified in silico from the head kidney transcriptome of the Antarctic teleost Trematomus bernacchii. The corresponding amino acid sequence, slightly longer than NK-lysins of other fish species, contains six cysteine residues that in mammalian counterparts form three disulphide bridges. Real time-PCR analysis indicated its predominant expression in T. bernacchii immune-related organs and tissues, with greatest mRNA abundance detected in gills and spleen. Instead of focusing on the full T. bernacchii derived NK-lysin mature molecule, we selected a 27 amino acid residue peptide (named NKL-WT), corresponding to the potent antibiotic NK-2 sequence found in human NK-lysin. Moreover, we designed a mutant peptide (named NKL-MUT) in which two alanine residues substitute the two cysteines found in the NKL-WT. The two peptides were obtained by solid phase organic synthesis to investigate their functional features. NKL-WT and NKL-MUT displayed antibacterial activity against the human pathogenic bacterium Enterococcus faecalis and the ESKAPE pathogen Acinetobacter baumannii, respectively. Moreover, at the determined Minimum Inhibitory Concentration and Minimum Bactericidal Concentration values against these pathogens, both peptides showed high selectivity as they did not exhibit any haemolytic activity on erythrocytes or cytotoxic activity against mammalian primary cell lines. Finally, the NKL-MUT selectively triggers the killing of the melanoma cell line B16F10 by means of a pro-apoptotic pathway at a concentration range in which no effects were found in normal mammalian cell lines. In conclusion, the two peptides could be considered as promising candidates in the fight against antibiotic resistance and tumour proliferative action, and also be used as innovative adjuvants, either to decrease chemotherapy side effects or to enhance anticancer drug activity.

A class of peptides designed to replicate and enhance the Receptor for Hyaluronic Acid Mediated Motility binding domain

The extra-cellular matrix (ECM) is a complex and rich microenvironment that is exposed and over-expressed across several injury or disease pathologies. Biomaterial therapeutics are often enriched with peptide binders to target the ECM with greater specificity. Hyaluronic acid (HA) is a major component of the ECM, yet to date, few HA adherent peptides have been discovered. A class of HA binding peptides was designed using B(X7)B hyaluronic acid binding domains inspired from the helical face of the Receptor for Hyaluronic Acid Mediated Motility (RHAMM). These peptides were bioengineered using a custom alpha helical net method, allowing for the enrichment of multiple B(X7)B domains and the optimization of contiguous and non-contiguous domain orientations. Unexpectedly, the molecules also exhibited the behaviour of nanofiber forming self-assembling peptides and were investigated for this characteristic. Ten 23-27 amino acid residue peptides were assessed. Simple molecular modelling was used to depict helical secondary structures. Binding assays were performed with varying concentrations (1-10 mg/mL) and extra-cellular matrices (HA, collagens I-IV, elastin, and Geltrex). Concentration mediated secondary structures were assessed using circular dichroism (CD), and higher order nanostructures were visualized using transmission electron microscopy (TEM). All peptides formed the initial apparent 310/alpha-helices, yet peptides 17x-3, 4, BHP3 and BHP4 were HA specific and potent (i.e., a significant effect) binders at increasing concentrations. These peptides shifted from apparent 310/alpha-helical structures at low concentration to beta-sheets at increasing concentration and also formed nanofibers which are noted as self-assembling structures. Several of the HA binding peptides outperformed our positive control (mPEP35) at 3-4 times higher concentrations, and were enhanced by self-assembly as each of these groups had observable nanofibers. Statement of significanceSpecific biomolecules or peptides have played a crucial role in developing materials or systems to deliver key drugs and therapeutics to a broad spectrum of diseases and disorders. In these diseased tissues, cells build protein/sugar networks, which are uniquely exposed and great targets to deliver drugs to. Hyaluronic acid (HA) is involved in every stage of injury and is abundant in cancer. To date, only two HA specific peptides have been discovered. In our work, we have designed a way to model and trace binding regions as they appear on the face of a helical peptide. Using this method we have created a family of peptides enriched with HA binding domains that stick with 3-4 higher affinity than those previously discovered.

Proteomic Identification of Plasma Components in Tachypleus tridentatus and Their Effects on the Longitudinal Bone Growth Rate in Rats

Tachypleus tridentatus (T. tridentatus) is a marine animal and traditional Chinese medicine. T. tridentatus plasma is a valuable resource for important medical and health-based functions. In this experiment, in order to evaluate the effect and mechanism of T. tridentatus plasma with respect to the promotion of bone tissue growth in rats, the processes of ultrafiltration and mass spectrometry were first used to separate and identify the components of T. tridentatus plasma. Then, a comparison of the effects of the T. tridentatus plasma samples, which each possessed different molecular weights, regarding the growth of the long bones of rats was conducted. Finally, transcriptomics, proteomics, and bioinformatics were all used to analyze the biological functions and related signaling pathways of the T. tridentatus plasma in order to promote rat bone growth. The results showed that the contents of amino acid residues in peptides are related to the growth promotion that was contained in the 10-30 kDa plasma group. Moreover, the T. tridentatus plasma samples were found to be higher in this respect than those in the whole plasma group. In addition, the 10-30 kDa plasma group could significantly promote bone growth activity in rats. The proteomic analysis showed that the proteins that were differentially expressed in the 10-30 kDa plasma group were mainly enriched in the PI3K-AKT signal pathway. Our study suggested that the T. tridentatus plasma possesses promising potential for the purposes of clinical use, whereby it can serve the role of a growth-promoting agent.

Supramolecular Detoxification of Macromolecular Biotoxin through the Complexation by a Large-Sized Macrocycle.

Biotoxins are diverse, complex, and hypertoxic, ultimately serving as grave and lasting menaces to humanity. Here, it is aimed to introduce a new detoxification methodology for macromolecular biotoxin through complexation by a very large macrocycle. A 25-mer peptide isolated from Lycosa erythrognatha spider venom (LyeTxI) is selected as the model macromolecular biotoxin. Quaterphen[4]arene, with a side length of ≈1.6nm, has a sufficient cavity to bind LyeTxI. Hence, the water-soluble derivative of Quaterphen[4]arene (H) is designed and synthesized. H exhibits an overall host-guest complexation toward LyeTxI, resulting in a considerably high association constant of (7.01±0.18)×107 m-1 . This encapsulation of peptide is interesting as traditional macrocycles can only engulf the amino acid residues of peptides due to their limited cavity size. In vitro assay verifies that complexation by H inhibits the interactions of LyeTxI with cell membranes, thereby reducing its cytotoxicity, suppressing hemolysis, and decreasing the release of lactate dehydrogenase. Notably, the intravenous administration of H has a significant therapeutic effect on LyeTxI-poisoned mice, alleviating inflammation and tissue damage, and markedly improving the survival rate from 10% to 80%. An efficient and potentially versatile approach is provided to detoxify macromolecular biotoxins, with giant macrocycle serving as an antidote.

Hit-to-Lead Short Peptides against Dengue Type 2 Envelope Protein: Computational and Experimental Investigations.

Data from the World Health Organisation show that the global incidence of dengue infection has risen drastically, with an estimated 400 million cases of dengue infection occurring annually. Despite this worrying trend, there is still no therapeutic treatment available. Herein, we investigated short peptide fragments with a varying total number of amino acid residues (peptide fragments) from previously reported dengue virus type 2 (DENV2) peptide-based inhibitors, DN58wt (GDSYIIIGVEPGQLKENWFKKGSSIGQMF), DN58opt (TWWCFYFCRRHHPFWFFYRHN), DS36wt (LITVNPIVTEKDSPVNIEAE), and DS36opt (RHWEQFYFRRRERKFWLFFW), aided by in silico approaches: peptide–protein molecular docking and 100 ns of molecular dynamics (MD) simulation via molecular mechanics using Poisson–Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) methods. A library of 11,699 peptide fragments was generated, subjected to in silico calculation, and the candidates with the excellent binding affinity and shown to be stable in the DI-DIII binding pocket of DENV2 envelope (E) protein were determined. Selected peptides were synthesised using conventional Fmoc solid-phase peptide chemistry, purified by RP-HPLC, and characterised using LCMS. In vitro studies followed, to test for the peptides’ toxicity and efficacy in inhibiting the DENV2 growth cycle. Our studies identified the electrostatic interaction (from free energy calculation) to be the driving stabilising force for the E protein–peptide interactions. Five key E protein residues were also identified that had the most interactions with the peptides: (polar) LYS36, ASN37, and ARG350, and (nonpolar) LEU351 and VAL354; these residues might play crucial roles in the effective binding interactions. One of the peptide fragments, DN58opt_8-13 (PFWFFYRH), showed the best inhibitory activity, at about 63% DENV2 plague reduction, compared with no treatment. This correlates well with the in silico studies in which the peptide possessed the lowest binding energy (−9.0 kcal/mol) and was maintained steadily within the binding pocket of DENV2 E protein during the MD simulations. This study demonstrates the use of computational studies to expand research on lead optimisation of antiviral peptides, thus explaining the inhibitory potential of the designed peptides.

Peptides as Therapeutic Agents for Atherosclerosis.

More than three decades ago, as a test for the amphipathic helix theory, an 18 amino acid residue peptide and its analogs were designed with no sequence homology to any of the exchangeable apolipoproteins. Based on the apolipoprotein A-I (the major protein component of high density lipoproteins, HDL) mimicking properties, they were termed as ApoA-I mimicking peptides. Several laboratories around the world started studying such de novo-designed peptides for their antiatherogenic properties. The present chapter describes the efforts in bringing these peptides as therapeutic agents for atherosclerosis and several lipid-mediated disorders.

Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection.

The Ebola virus VP30 protein interacts with the viral nucleoprotein and with host protein RBBP6 via PPxPxY motifs that adopt non-canonical orientations, as compared to other proline-rich motifs. An affinity tag-purification mass spectrometry approach identified additional PPxPxY-containing host proteins hnRNP L, hnRNPUL1, and PEG10, as VP30 interactors. hnRNP L and PEG10, like RBBP6, inhibit viral RNA synthesis and EBOV infection, whereas hnRNPUL1 enhances. RBBP6 and hnRNP L modulate VP30 phosphorylation, increase viral transcription, andexert additive effects on viral RNA synthesis. PEG10 has more modest inhibitory effects on EBOV replication. hnRNPUL1 positively affects viral RNA synthesis but in a VP30-independent manner. Binding studies demonstrate variable capacity of the PPxPxY motifs from these proteins to bind VP30, define PxPPPPxY as an optimal binding motif, and identify the fifth proline and the tyrosine as most critical for interaction. Competition binding and hydrogen-deuterium exchange mass spectrometry studies demonstrate that each protein binds a similar interface on VP30. VP30 therefore presents a novel proline recognition domain that is targeted by multiple host proteins to modulate viral transcription.

Oxidative Damage of S‐Containing Amino Acids by the Environmental Radical NO3.: A Kinetic, Product and Computational Study

AbstractMethionine, cysteine and cystine, which were acetylated at the N‐terminus and methylated at the C‐terminus, react rapidly with the environmental nitrate radical (NO3.) with rate coefficients of 7.7×109, 3.4×109 and 2.0×109 M−1 s−1, respectively, in acetonitrile. Methionine (Ac−Met−OMe) is successively oxidized via the sulfoxide (Ac−MetO−Me) to the sulfone (Ac−MetO2−OMe), with the latter step being also extremely fast with a rate coefficient of 1.2×109 M−1 s−1. Computations predict formation of an initial charge transfer complex between NO3. and the S or SO moiety in Ac‐Met‐OMe, Ac‐MetO‐OMe and cystine (Ac−Cys(S−S)Cys‐OMe), respectively, which is followed by simultaneous S−O bond formation and NO2. expulsion. Calculations for the reaction of cysteine (Ac‐Cys‐OMe) with NO3. revealed side‐chain oxidation to give a thiyl radical or a sulfenic acid as likely pathways. These findings highlight the potential harmful impact of NO2./O3 pollution on S‐containing amino acid residues in peptides.

Selected β2-, β3- and β2,3-Amino Acid Heterocyclic Derivatives and Their Biological Perspective.

Heterocyclic moieties, especially five and six-membered rings containing nitrogen, oxygen or sulfur atoms, are broadly distributed in nature. Among them, synthetic and natural alike are pharmacologically active compounds and have always been at the forefront of attention due to their pharmacological properties. Heterocycles can be divided into different groups based on the presence of characteristic structural motifs. The presence of β-amino acid and heterocyclic core in one compound is very interesting; additionally, it very often plays a vital role in their biological activity. Usually, such compounds are not considered to be chemicals containing a β-amino acid motif; however, considering them as this class of compounds may open new routes of their preparation and application as new drug precursors or even drugs. The possibility of their application as nonproteinogenic amino acid residues in peptide or peptide derivatives synthesis to prepare a new class of compounds is also promising. This review highlights the actual state of knowledge about β-amino acid moiety-containing heterocycles presenting antiviral, anti-inflammatory, antibacterial compounds, anaplastic lymphoma kinase (ALK) inhibitors, as well as agonist and antagonists of the receptors.

Small Molecular Weight Compounds Antagonistic to Amyloid Peptide<sub>25-35</sub>

High levels of the neurotoxic beta-amyloid protein (Aβ) in patients with Alzheimer’s disease present a significant therapeutic target, although the protein is unlikely to be the sole instigator of this condition. Aβ initiates cell receptor and synapse dysfunction, and causes mitochondrial damage within neurons. Neurotransmitters and various small molecular weight compounds ameliorate the effects of Aβ on cell membranes. This study uses a molecular modeling technique to compare the structures of Aβ25-35 and compounds known to antagonize properties of the polypeptide. Compounds provide good fits to the peptide amino acid residues, revealing planarity in their linear structures and fitting points. Compounds and polypeptide share relative molecular similarity, affinity for receptors and apoptosis modulating properties indicative of their potential for competition at neuron membrane sites. The therapeutic targeting of Aβ by small molecular weight compounds may benefit from a multi-drug approach.

Ischemia-induced retinal injury is attenuated by Neurovespina, a peptide from the venom of the social wasp Polybia occidentalis

Neurovespina is a synthetic peptide modified from Occidentalin-1202, a nine amino acid residue peptide isolated from the venom of the social wasp Polybia occidentalis. Previous studies showed that this peptide has a neuroprotective effect on the central nervous system, but its action on the eye has not been explored. So, the objective of this work was to investigate the neuroprotective effect of Neurovespina on the retina and its angiogenic potential in the chicken chorioallantoic membrane (CAM). Retinal ischemia was induced in rats by acute elevation of intraocular pressure (IOP). Electroretinography (ERG) measurements, histopathological and immunohistochemical analysis, and transmission electronic microscopy (TEM) records were performed to check the neuroprotection effect of Neurovespina in the retina of the animals. The angiogenic activity of the peptide was investigated by CAM assay. The results showed that Neurovespina was able to reduce the effects induced by ischemic injury, preventing the reduction of a- and b-waves in the scotopic ERG. Histopathological and immunohistochemistry assays showed that Neurovespina, mainly at 60 μg/ml, protected all layers of the retina. The CAM assay revealed that the peptide promoted the reduction of CAM vessels. So, Neurovespina was able to protect retinal cells from ischemic insult and has an antiangiogenic effect, which can be considered as a promising neuroprotective agent for intravitreal application.

Дизайн, синтез дипептидных миметиков 1-й петли фактора роста нервов и изучение их нейропротекторной и дифференцирующей активности <i>in vitro</i>

Ранее в НИИ фармакологии имени В. В. Закусова был создан димерный дипептидный миметик наиболее экспонированной 4-й петли фактора роста нервов (NGF) гексаметилендиамид бис-(N-моносукцинил-L-глутамил-L-лизина) (ГК-2), активирующий специфические TrkA рецепторы и обладающий нейропротекторной активностью in vitro (10–5 – 10–9 М) и in vivo (0,1 – 10 мг/кг ip, po). В данной работе на основе бета-изгиба (-Lys32-Gly33-Lys34-Glu35-) 1-й петли NGF сконструирован и синтезирован ее миметик гексаметилендиамид бис-(N-аминокапроил-глицил-L-лизина) (ГК-6). В структуре ГК-6 был сохранен центральный дипептидный фрагмент бета-изгиба -Gly33-Lys34-, остаток -Lys32 заменен на его биоизостер — остаток 6-аминокапроновой кислоты и димерная структура NGF воспроизведена димеризацией по С-концу с помощью бивалентного гексаметилендиаминового спейсера. Для изучения связи структуры и активности ГК-6 проведена последовательная замена боковых групп а.о. пептида на водород и получены гексаметилендиамиды бис-(N-ацетил-глицил-L-лизина) (ГТС-611) и бис-(N-аминокапроил-глицил-глицина) (ГТС-613). Миметик ГК-6 и его аналог ГТС-613, содержащие в своей структуре N-аминокапроильный радикал, обладают нейропротекторным эффектом в концентрациях 10–6 и 10–5 М в условиях окислительного стресса на культуре нейронов HT22. Дипептид ГТС-611, в котором аминокапроильный фрагмент заменен на ацетильный, в этих условиях нейропротекторной активностью не обладал, что говорит о важности Lys32 в NGF для ее проявления. В отличие от миметика 4-й петли ГК-2, миметики 1-й петли ГК-6 и ГТС-611 проявляли дифференцировочную активность на клетках PC12.

Modulation of co-stimulatory signal from CD2-CD58 proteins by a grafted peptide.

Peptides were designed to inhibit the protein-protein interaction of CD2 and CD58 to modulate the immune response. This work involved the design and synthesis of eight different peptides by replacing each amino acid residue in peptide 6 with alanine as well as grafting the peptide to the sunflower trypsin-inhibitor framework. From the alanine scanning studies, mutation at position 2 of the peptide was shown to result in increased potency to inhibit cell adhesion interactions. The most potent peptide from the alanine scanning was further studied for its detailed three-dimensional structure and binding to CD58 protein using surface plasmon resonance and flow cytometry. This peptide was used to graft to the sunflower trypsin inhibitor to improve the stability of the peptide. The grafted peptide, SFTI-a1, was further studied for its potency as well as its thermal, chemical, and enzymatic stability. The grafted peptide exhibited improved activity compared to our previously grafted peptide and was stable against thermal and enzymatic degradation.

Photochemically-Generated Silver Chloride Nanoparticles Stabilized by a Peptide Inhibitor of Cell Division and Its Antimicrobial Properties

The 40 amino acid residues peptide MciZ (Mother Cell Inhibitor of FtsZ) represents a promising antibacterial agent as it is an effective inhibitor of bacterial cell division, Z-ring formation and localization. However, its efficacy is limited to Gram-positive bacteria as MciZ is unable to penetrate into Gram-negative organisms. In this study, we report the synthesis of plasmonic silver chloride nanoparticles stabilized by MciZ (NP/MciZ). NP/MciZ were synthesized using a fast and green route under blue light irradiation. Electron microscopy showed that NP/MciZ were enveloped by a peptide layer responsible for colloidal stability. X-ray diffraction analysis showed that silver chloride nanoparticles were crystalline in nature with small proportion of metallic silver. NP/MciZ showed a dose-dependent cytotoxicity against mammalian VERO cells. However, NP/MciZ exhibited remarkable antibacterial activity against Gram-positive bacterium B. megaterium comparable to MciZ. Furthermore, NP/MciZ showed similar antimicrobial activity against the Gram-negative bacterium E. coli and the yeast C. albicans. The photochemically-generated NP/MciZ presented here is a new organic–inorganic hybrid nanomaterial and has potential for biomedical or other applications.

Cover Feature: Reductant‐Induced Free Radical Fluoroalkylation of Nitrogen Heterocycles and Innate Aromatic Amino Acid Residues in Peptides and Proteins (Chem. Eur. J. 69/2019)

In an underwater sea scene, the key process of protein functionalization on tryptophan is shown. The follow-up click reaction by using the pink reagent carrying a payload delivers the conjugate of choice. Realistic depiction of hypervalent iodine reagents includes the T-shape geometry on the iodine atom and the azido-containing fluoroalkyl group. On the seabed there are side products from the reagent after the reaction with the protein. More information can be found in the Full Paper by P. Novák, P. Beier, et al. on page 15779.

Reductant-Induced Free Radical Fluoroalkylation of Nitrogen Heterocycles and Innate Aromatic Amino Acid Residues in Peptides and Proteins.

A series of fluoroalkylated cyclic λ3 -iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition-metal-free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.