Designing peptides to meet the challenge of the next generation of druggable targets

Jul 30, 2020 9:49:00 AM

Targeting protein–protein interactions (PPIs) is a new challenge in expanding druggable space. Cyclic peptides show promise in targeting PPIs and to better understand their structure–activity relationships a research team at Tufts University, USA, has analyzed a series of designed, well-structured cyclic hexapeptides and use simulations and experimental techniques to understand their global structural ensembles. They discovered a previously unappreciated role for β-branched residues in stabilizing specific conformations of cyclic hexapeptides, and their approach shows promise in the prediction of structure–activity relationships for drug development. Their work was rewarded by being on the front cover of Biophysical Journal, Volume 116, Issue 3.

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Topics: Peptide synthesis, Protein-Protein Interactions (PPIs), Tribute peptide synthesizer, Cyclic peptides

Peptide inhibitor of methylation casts new light on epigenetic-based cancer therapy

Jul 1, 2020 12:00:00 AM

The first peptide-derived epigenetic drug (Romidepsin) was approved in 2009 for the treatment of cutaneous T cell lymphomas (CTCL), and in 2011 for peripheral T cell lymphomas (PTCL) (2). Romidepsin also has potential in the treatment of other kinds of cancer, lung fibrosis, and Epstein-Barr infections. Currently, it is the only FDA-approved peptide medicine specifically designed to target epigenetic effects. Nesiritide, a peptide originally approved in 2001 for the symptomatic treatment of acute decompensated heart failure due to its vasodilating activity has since been repurposed due to its epigenetic effects. These peptides are not yet approved in the European Union by the EMA.

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

Unlocking aggregation in amyloid peptides opens up Alzheimer’s research

Sep 30, 2019 9:00:00 AM

Alzheimer's is a progressive degenerative disease of the brain that accounts for 60–80% of dementia cases, which cover a range of cognitive disabilities including memory loss (1). Alzheimer's is the sixth leading cause of death in the United States, with an expected life expectancy of 4–8 years after diagnosis.This disease is not a normal part of aging, and approximately 200,000 Americans under the age of 65 have younger-onset Alzheimer’s disease. There is currently no cure, but symptoms can be treated and great efforts are being made worldwide to improve treatment, delay onset, and ultimately prevent the disease from developing.The amyloid beta peptides involved in Alzheimer’s disease are prone to aggregation, challenging both synthesis and purification. A group based in Auckland New Zealand therefore developed a method to reversibly introduce double linkers into the synthetic peptide that reduce aggregation and improve solubility, resulting in higher yields and purity. 

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Topics: Peptide synthesis, Alzheimer's disease, Tribute peptide synthesizer, SPPS, Amyloid peptides, Pseudoproline

Overcoming opioid side effects with combination peptide therapy

Aug 20, 2019 8:30:00 AM

Unrelieved pain is a major global healthcare problem. There are two types of pain: acute pain, which is typical after surgery and trauma and chronic or recurring pain, which is common in individuals suffering from osteo- and rheumatoid arthritis, those with spine problems, and can be developed after operations and injuries. The problem is so great that chronic and recurrent pain is regarded as a disease in its own right. Apart from the burden of suffering, chronic pain results in a considerable cost to society that is on a par with cancer or cardiovascular disease by affecting one in five adults.

Opioids are the analgesics most prescribed to treat moderate to severe pain but their use leads to a number of debilitating side effects, diminishing efficacy, and also the risk of abuse and misuse. A research team at Université de Sherbrooke in Canada has investigated combining the prototypical opioid morphine and an analgesic neurotensin brain-penetrant peptide analog to treat pain. They discovered that co-administration resulted in an additive analgesic response that permitted the dosing of morphine to be reduced and also decreased the level of a typical adverse side effect, constipation.

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Topics: Peptide synthesis, SPPS, Symphony peptide synthesizer, Combination peptide therapy, Pain treatment

5 factors to consider when choosing a peptide synthesizer

Apr 24, 2019 11:00:00 AM

Choosing a peptide synthesizer to meet your specific needs can be a daunting task. Here are some key factors to consider to be able to synthesize high quality peptides in the number and scale that matches your applications.

1. The question of throughput and parallel synthesis

Different applications and phases of research require different numbers of peptides. A peptide drug discovery program may involve screening hundreds (or even thousands) of peptides to find hits, followed by optimizing structure-activity relationships (SAR) with focused libraries to identify a single candidate that can be advanced to the clinic. The key to success is therefore to choose a synthesizer that has reaction vessels that can deliver the level of parallel synthesis you need to match your application1.

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Topics: Prelude x, Symphony X, Peptide synthesis, Tribute, SPPS, Sonata XT, Real-time UV monitoring

Reaching the target – a novel cell penetration assay provides new insights into the design and intracellular compartmentalization of biotherapeutics

Feb 21, 2019 4:21:51 PM

There have been massive advances in the development of biotherapeutics but progress has been slow in targeting intracellular processes due in part to the difficulty of measuring cell penetration and distribution between intracellular compartments and organelles. A research group based at Tufts University, USA, has developed a novel assay, the Chloroalkane Penetration Assay (CAPA), as a powerful tool to meet this challenge. They have shown how CAPA can help in following the modulation of biomolecule cell penetration, including structure-penetration profiling of bioactive stapled peptides and peptides fused to cell-penetrating sequences, measuring the effect of environmental factors on penetration, and tracing the movement of potential biotherapeutics between organelles.

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Topics: Peptide synthesis, Tribute peptide synthesizer, Biotherapeutics development, Cell penetration assay

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, Tribute peptide synthesizer, Gene therapy, Cell penetrating peptide, 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, PS3 peptide synthesizer, CXCR4-KLA peptide, Ovarian cancer, cytotoxic drug resistance