Cyclic hexapeptide mimics designed to disrupt HIV-1 integrase interaction with key cell protein involved in viral import

Dec 7, 2018 2:00:00 PM

Efforts to fight HIV infection have included the development of drugs that disrupt the integration of proviral DNA into the host genome. Researchers based at Monash Institute of Pharmaceutical Sciences, Australia, have developed cyclic hexapeptides that disrupt the interaction between the viral integrase and a key protein involved in viral import, lens epithelium-derived growth factor (LEDGF/p75). The peptides closely mimicked the structure of the LEDGF binding domain but their low affinities indicate that more interactions must be included in order to achieve the potency needed for an effective drug.

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Topics: Peptide synthesis, PS3 peptide synthesizer, Cyclic hexapeptides, HIV-1 integrase, LEDGF/p75

Cationic cell penetrating peptides with fatty acyl groups improve siRNA-delivery by chitosan for gene therapy

Oct 16, 2018 10:00:00 AM

After thirty years of promise and setbacks, a number of gene therapies for inherited immune disorders, like hemophilia, eye and neurodegenerative disorders, and lymphoid cancers have recently been approved in the United States and Europe or are anticipated to receive approval in the near future. One approach to gene therapy is to suppress the expression of specific proteins by gene silencing using siRNA. Viral delivery systems can have issues of immunogenicity and mutagenesis. This has stimulated the development of non-viral delivery systems. El-Sayed and collaborators based in Egypt and the USA have shown that chitosan complexed with fatty-acyl derivatives of a cationic cell-penetrating peptide, CGKRK, shows promise as a method for delivering intact short interfering RNA (siRNA) to breast cancer cells in vitro.

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Topics: Peptide synthesis, Gene therapy, Cell penetrating peptide, Tribute peptide synthesizer, siRNA delivery

Hydrocarbon stapled peptides: a new strategy to advance antimicrobial therapy

Sep 25, 2018 3:00:00 PM

New approaches are needed in the fight against antibiotic resistance. One is the use of short antimicrobial peptides that selectively disrupt the membranes of bacteria. A collaboration between the Hospital for Sick Children, Toronto, and the University of Toronto has led to new insights into how antimicrobial peptide activity can be modulated using stapling and substitution of residues. This is a promising approach in the development of new peptide therapeutics.
Antimicrobial peptides are generally short (6–50 aa), with one of the largest categories being cationic antimicrobial peptides (CAPs). These peptides are rich in positively charged amino acids such as Lys and Arg and also have a hydrophobic region rich in large aromatics. The CAPs adopt an α-helix that folds to present the positively charged face to the aqueous medium while the hydrophobic face specifically targets the abundant negatively charged lipid head groups in bacterial membranes and weakens or disrupts the membrane to kill the bacterium. In this review article, the authors report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart.

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Topics: Peptide synthesis, PS3 peptide synthesizer, Stapled peptides, Antimicrobial therapy, peptide therapeutics

Bifunctional peptide targets CXCR4 drug-resistant cancer stem cells to fight resistance to conventional chemotherapy

Jul 30, 2018 3:00:00 PM

Ovarian cancer (OVC) patients often acquire resistance to cytotoxic drugs such as cisplatin, doxorubicin, and paclitaxel within a year, leading to a disease recurrence rate of up to 80%. Hyun Hee Lee and colleagues at Weill Cornell Medicine, New York, USA have used a peptide to target the G-protein coupled receptor 4 (CXCR4) that plays a significant role in promoting tumorigenesis and drug resistance. The research team has shown that targeting a CXCR4High cancer stem cell population with a selective peptide resulted in a synergistic cytotoxic effect when combined with chemotherapy agents such as doxorubicin and cisplatin. This is a promising approach in fighting drug resistance and improving treatment outcomes.

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Topics: Peptide synthesis, CXCR4-KLA peptide, Ovarian cancer, PS3 peptide synthesizer, cytotoxic drug resistance

A peptide targeting FGFR2 receptor promises early detection of esophageal adenocarcinoma

Jun 28, 2018 10:00:00 AM

The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing, with 450,000 new cases diagnosed and 400,000 deaths reported annually worldwide. Early detection is complicated by difficulty in detecting the flat premalignant lesions. However, the overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in disease progression. A team comprising researchers based at the University of Michigan, USA and The Fourth Military Medical University, China, have identified a peptide that binds with high specificity to the extracellular domain of FGFR2, making this peptide a promising clinical imaging agent for early detection of esophageal adenocarcinoma.

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Topics: Cancer, FGFR2 receptor, PS3 peptide synthesizer, esophageal adenocarcinoma, Clinical imaging agent, Peptide synthesis

Mapping neuropeptide-receptor and agonist binding: peptide synthesis strategies to guide the design of novel modulators of appetite regulation

May 8, 2018 9:00:00 AM

With 30–70% of adults in the European Union designated overweight and 10–30% obese (WHO), and more than one third of US adults obese (CDC), the global obesity epidemic has stimulated much research into the fundamentals of appetite regulation. Bo Xu and colleagues, based at Uppsala University in Sweden and collaborating with Novo Nordisk A/S in Denmark, have studied the interaction between the agonist neuropeptide Y (NPY) and the human receptor Y2 involved in appetite regulation. Using a combination of computational modeling, peptide chemistry and in vitro pharmacology analysis the research team has gained insight into interactions that promise to guide the design of novel modulators to fight obesity.

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Topics: Peptide synthesis, Human neuropeptide Y, NPY, Obesity, Appetite regulation, Prelude x

Inhibitory peptides help identify receptor complex vital to male fertility

Mar 12, 2018 9:00:00 AM

The acrosome reaction is critical for the sperm to penetrate the female egg and fertilize it. Progesterone plays a key role in the acrosome reaction, but how this works has been unclear since spermatozoa lack classical progesterone receptors. Wenming Xu and collaborators at Sichuan University, China, The Chinese University of Hong Kong, and the Australian National University, have shown that the progesterone-induced Ca2+ influx required for the acrosome reaction involves the progesterone receptor or modulator, gamma-aminobutyric acid type A (GABAA) receptor delta subunit (GABRD), in combination with the P2X2 receptor.
The first confirmation that delta subunits were involved in the Ca2+influx came with an experiment that demonstrated that increased intracellular levels of Ca2+ in spermatozoa after progesterone stimulation were suppressed by the δ(392-422) inhibitory peptide but unaffected by a scrambled δ control peptide or a Υ2-peptide.

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Topics: Peptide synthesis, Symphony X peptide synthesizer, The acrosome reaction, Male fertility, Inhibitory peptides

Peptide drug leads with increased inhibitory properties synthesized using a divergent strategy

Feb 6, 2018 2:01:22 PM

Protein-protein interactions (PPI) play a major role in regulating many cellular processes, which makes them attractive druggable targets. The large surface area involved in PPIs, however, demands high selectivity of large drug leads such as proteins that can be difficult to modify and fine-tune. To demonstrate a solution to this problem, Christian Tornøe and his colleagues at Novo Nordisk in Denmark have synthesized analogues of Bowman-Birk protease inhibitor (BBI) by using native chemical ligation of peptide hydrazides to link together peptide building blocks to generate several analogues of BBI. This approach required fewer reaction steps than a linear synthesis strategy, and could be used to graft a specific region of a potent trypsin inhibitor onto the α- chymotrypsin-binding loop of BBI that boosted its inhibitory effect four-fold. 

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Topics: Protein-Protein Interactions (PPIs), Prelude peptide synthesizer, Peptide synthesis

Enabling identification of phosphorylated cysteine: Novel chemoselective synthetic and analytical methods

Dec 5, 2017 10:32:31 AM

Protein phosphorylation plays a key role in the regulation of signaling pathways and many other cellular processes. Studies of phosphorylation have focused on serine, threonine and tyrosine amino-acid side chains, while the phosphorylation of other amino acids, such as phospho-histidine (pHis), -arginine (pArg), -lysine (pLys) and -cysteine (pCys), is less well understood. Studies have been hindered by technical limitations, primarily acid lability. To address this problem, Jordi Bertran-Vicente and colleagues have developed a novel chemoselective and stereochemically defined phosphorylation strategy for Cys residues.  The method employs the nucleophilic reactivity of P(III)-reagents (phosphites) with electrophilic disulfides. The research team has also developed a mass spectrometry-based proteomic approach to identify and characterize pCys sites that naturally occur in peptides. 

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Topics: Peptide synthesis, Tribute, Tribute peptide synthesizer, Protein phosphorylation, pCys

Green Chemistry: healthier chemists with every peptide synthesized

Sep 27, 2017 3:00:00 PM

As solid phase peptide synthesis (SPPS) typically uses an excess of reagents to drive the completion of these reactions, there is a need for the use of a large amount of solvents, most of which are hazardous. In fact, solvents make up the major component of the reaction mixture representing 80−90% of the nonaqueous mass, as concluded in a survey by GSK in 2007 about the materials used for the manufacturing of active pharmaceutical ingredients (APIs). Benzotriazols (and variants) are frequently used as coupling agents for peptide syntheses in the pharmaceutical industry. However, their safety profile must be carefully considered as these compounds display explosive properties, when heated under defined confinement or when subjected to mechanical stimulus that leads to restrictions for their shipping and handling. In addition, a variety of allergic responses have been reported from exposure to some coupling agents. Moreover, residues of the starting material 1-Chloro-2-nitrobenzene and hydrazine, used for the synthesis of bezotriazol moieties are known to have toxic effects, even at parts per billion (ppb) levels. For example, irritating effects on the mucous membrane, as well as skin irritation, have been reported when exposed to the dust of HOBt.


Taking into consideration the hazardous potential of the essential benzotriazole-based coupling reagents, our partner Luxembourg Biotechnologies Ltd. decided to reduce the environmental and health impact of these chemicals by developing compounds that are safer yet achieve comparable results as HOBt. With these compounds we move towards our goals to create a healthy and safe working environment and achieve a zero-disaster risk that is implemented in local policies, training, lab goal setting, and performance evaluation.

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Topics: Peptide synthesis, green chemistry, Oxyma-based reagents, solid-phase peptide synthesis