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

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, pCys, Protein phosphorylation

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, solid-phase peptide synthesis, green chemistry, Oxyma-based reagents

Multifunctional thermoresponsive peptide hydrogels designed to meet the demands of biomedical applications

Sep 6, 2017 10:00:00 AM

The uncertainties of the long-term stability and effects of artificial materials in the human body have stimulated research into more natural materials for many biomedical applications. This search has lead to the discovery of peptide hydrogels, a highly promising family of constructs that are capable of self-assembly, typically into β-sheets, and can emulate the properties of natural materials such as collagen. Fine-tuning the mechanical properties of hydrogels to solve biomedical problems is, however, a real challenge. A team headed by researchers at the University of Auckland in New Zealand has come one step further with peptide hydrogels that are reversibly thermoresponsive. Their innovative hydrogels are based on multifunctional peptides that combine a hydrogel-forming β-sheet peptide segment, an enzyme substrate that enables biodegradation, and a RGD sequence to promote cell adhesion.

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Topics: Peptide synthesis, PS3 peptide synthesizer, Peptide synthesizer, β-sheet-forming peptides, Multifunctional peptides, Hydrogel

The CWR tripeptide - a promising activator of SIRT1 in the fight against Alzheimer’s disease

Aug 10, 2017 3:00:00 PM

The list of scientific publications by users of our peptide synthesizers is growing steadily.This review article is based on a recent article in the European Journal of Medicinal Chemistry by Rahul Kumar and colleagues at All India Institute of Medical Sciences and School of Computational and Integrative Sciences, Jawaharlal Nehru University in New Delhi, India.

In this study, Rahul Kumar and his colleagues designed and synthesized a novel peptide SIRT1 activator. SIRT1 has been shown to have a protective role against Alzheimer's disease.The peptide, CWR, was tested for its effect on the activity of recombinant SIRT1 protein and also determining its cytotoxicity. CWR was found to be a potent allosteric activator of SIRT1 both by molecular docking and in vitro analysis, increased cell viability and no toxicity to human erythrocytes were also observed.

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Topics: Peptide synthesis, PS3 peptide synthesizer, Alzheimer's disease, SIRT1 activator

Designer peptoids-improving on Mother Nature

Jul 27, 2017 10:00:00 AM

Peptoids offer a way of improving on nature in a range of biomedical applications such as antimicrobial agents, nanomaterials and diagnosis and treatment of a wide number of cancers.Over 150 peptoid-related papers are now being published per year, and in total, there are over 1700 publications.

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Topics: Peptide synthesis, Peptoids, Symphony X peptide synthesizer

Amyloid formation in Alzheimer’s may be modulated by vesicles formed by cholesterol derivatives

Jul 17, 2017 3:59:32 PM

Anomalous protein aggregation has been pinpointed as a prime cause of a number of serious neurodegenerative diseases that include Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob. In the case of Alzheimer’s, protein aggregation starts with cleavage of an amyloid precursor protein (APP) by a secretase to form amyloid-β (Aβ), a family of peptides that form toxic fibrillar plaques, leading to progressive neuron degeneration. This insight has hastened the search for methods to prevent plaque formation. The cholesterol-rich membrane microdomains that promote secretase activity appear to be involved. Added to that, free cholesterol in the cytoplasm can promote the aggregation of Aβ peptides into fibrils, and cholesterol can interact directly with APP and Aβ amyloid fibrils. With this in mind, Elbassal and colleagues at Florida Atlantic University, USA, investigated how cholesterol and its derivatives could affect the formation of fibrils. They showed that the structural properties of the cholesterol-derivative vesicles, including surface charge and vesicle size, are critical in regulating their effect on Aβ40 aggregation kinetics.

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Topics: Peptide synthesis, PS3 peptide synthesizer, Alzheimer's disease, Amyloid formation

Advancing drug targets for peptide-peptide interactions: Peptide flexibility is key in inhibiting the MDM2/p53 interaction

Jun 26, 2017 2:00:00 PM

The search for new drug classes has gone beyond the classically druggable genome, which appears to be limited to around 1,500 proteins. One route is the development of molecules that interfere with the Protein-Protein Interactions (PPIs) that are critical to all cellular processes, such as the regulation of cell growth, DNA replication, transcriptional activation, protein folding, and transmembrane signaling. One PPI-based drug target that involves a well-defined secondary structure is the interaction between the p53 tumor suppressor, the so-called “guardian of the genome” involved in programmed cell death, and MDM2, an important negative regulator of p53. This interaction involves a “hot spot triad” of three residues, Phe19, Trp23 and Leu26, on one face of the α-helical region of p53. Mimicking this region with a peptide became the focus of a collaborative effort between University of Gothenburg, Sweden and St. Jude Children’s Research Hospital in Tennessee, USA and resulted in key insights into the balanced peptide design required to achieve effective PPI inhibition (Danelius et al, 2016).

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Topics: Peptide synthesis, PS3 peptide synthesizer, Protein-Protein Interactions (PPIs), peptide-based PPI inhibitors

Expanding bio-functionality of peptide-based polyelectrolyte complexes through changes in chirality

Jun 9, 2017 8:47:49 AM

In the search for ways to handle soft materials at the nano-level, Polyelectrolyte Complexes (PECs) offer a lot of promise. They self-assemble and their enormous diversity of structure and chemical composition enable functionality to be fine-tuned. The biocompatibility and biodegradability of peptide polymer PECs means they are particularly useful in such as food additive encapsulation, micellar drug delivery, and scaffolding cell growth for tissue engineering. The physical properties of peptide polymer PECs can be modulated based on many factors. Naomi Pacalin, Lorraine Leon, and Matthew Tirrell at the University of Chicago, USA, have shown that changing the chirality of peptide polymer PECs alters the strength of polymer chain interactions, allowing chirality to be used to tailor polymers to have the precise properties needed for a particular application (Eur. Phys. J. Spec. Top., 2016, 225:1805).

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Topics: Peptide synthesis, PS3 peptide synthesizer, peptide-based polyelectrolyte complexes