September 1, 2009 (Vol. 29, No. 15)

Recent Strides in Research and Emerging Technologies Energize a Once Stagnating Field

Peptide drug discovery is a huge endeavor—and a huge field. Researchers and tool/technology developers alike traveled to Seoul recently for BIT Life Sciences’ “PepCon” meeting, where advances and trends in peptide and protein research were shared.

There was a time when the thought of the human brain as a giant endocrine gland was enough to make neuroscientists cringe. Now, it is well accepted that the brain produces large quantities of a diverse array of proteins, peptides, and steroidal hormones that have endocrine or autocrine function. Both functions require specific receptors in the brain to interpret signals from the hormones. These receptors are also drug discovery targets. For example, the search for agonists and antagonists of brain-localized opioid receptors has been ongoing since the nineteenth century.

Opioid peptide-based drug discovery is a popular field—and one in which Peter W. Schiller, Ph.D., director of the laboratory of chemical biology and peptide research at the Clinical Research Institute of Montreal, professor of pharmacology at University of Montreal, and adjunct professor, Center for Drug Discovery, Northeastern University, is actively engaged.

In a collaboration with Hazel Szeto, M.D., Ph.D., professor of pharmacology at Cornell University, Dr. Schiller codiscovered Schiller-Szeto (SS) peptides. One of the more promising SS peptides, SS02, is now being investigated in preclinical studies by both labs. According to Dr. Schiller, SS02 is a tetrapeptide that, when given intrathecally or subcutaneously, is a systemically active, potent, long-lasting mu-opioid agonist in rodents.

“SS02 produces centrally mediated analgesic effects, indicating that it was able to cross the blood-brain barrier,” he said, adding that “this peptide, like all amino acid mu agonists, still produced analgesic tolerance but did not produce cross-tolerance with many morphine drugs, indicating that we can use this drug to treat patients who have become tolerant to morphine drugs.”

Another obviously hot area of brain research today is focused on understanding the pathogenesis of neurodegenerative diseases. Radmila Mileusnic, D.Sc., reader in neurobiology, department of life sciences, The Open University, U.K., is using peptides as a tool to determine the role of a specific protein in the pathogenesis of Alzheimer’s disease (AD).

In a major discovery, Dr. Mileusnic’s research team demonstrated that one of these peptides, a palindromic tripeptide RER (arg-glu-arg) that is homologous to amino acid 328-330 in the growth-promoting region of the amyloid precursor protein (APP 328-330), protects against the amnestic effect of injected Abeta 1-42.

To determine the peptide’s biological function, as well as to increase its efficacy as a potential memory enhancer, the group has created a number of compounds that are structurally related to RER. In one such compound, the N-terminal portion of Abeta was acetylated—a formulation effective in prolonging memory retention, which protects against the amnestic effects of Abeta. “More importantly, acetylated RER was active when injected peripherally (as well as centrally) and rapidly transported across the blood-brain barrier,” said Dr. Mileusnic.

While exploring D- and L-stereoisomeric forms of RER peptide, the group found that “acetylated-rER [Ac-rER, where the lower case indicates the D-isomeric form of the amino acid] was rapidly transported across the blood-brain barrier and protected against Abeta-induced memory loss, and enhanced retention—Ac-ReR, Ac-REr, and Ac-rer, however, were inactive. We strongly believe that our data further strengthens the case for considering Ac-rER as the basis for a potential therapeutic agent in the early stages of AD,” said Dr. Mileusnic.

With any form of drug discovery involving a biological, it is typically necessary to obtain large quantities of the purified prospective drug. In the case of peptide drug discovery, the peptide may either be synthesized or purified, with synthesis being the easier method for obtaining a sufficient quantity of pure peptide.

LC Sciences has developed a peptide array technology that involves in situ high-density peptide synthesis and multiplex protein assays carried out in a microfluidic picoliter-scale microarray. According to the company, PepArray products and services allow for the synthesis of thousands of custom peptides. The technology also allows users to assay the synthesized peptides against specific drug targets.

“Not only is this technology enabling therapeutic synthetic peptide screening through rapid design, synthesis, and screening of diverse peptides and peptide analogs against important therapeutic targets, but it is also enabling the use of peptides as tools for study of kinases, antibodies and autoantibodies, phosphopeptide-binding proteins, and other pathway-signaling molecules,” said Xiaolian Gao, CSO of LC Sciences and director of the Keck/IMD NMR Center at the University of Houston.

According to Gao, the combination of the microfluidic design of the chip itself, a photo-generated acid synthesis chemistry (that makes use of conventional amino acid building blocks), and digital photolithography, are what make the PepArray technology unique.

PepArray™ is an assay reaction device that allows thousands of titration reactions, multiple-step enzymatic reactions, and other biochemical reactions to be performed simultaneously in a single experiment.


Detecting new biomarkers is the focus of many research groups. Peptides and proteins can be biomarkers in biological fluids such as serum or plasma, but like other biomarkers they may exist in low abundance, making their discovery quite challenging. According to Sigma-Aldrich, its Immunodepletion technology addresses that challenge. At the center of Immunodepletion is a novel, tandem IgY14-Supermix immunoaffinity separation system that is reportedly capable of depleting more than 90 highly abundant and moderately abundant proteins from serum, facilitating the discovery of low-abundance biomarkers.

“The IgY antibody used in the technology was developed in chickens, resulting in high specificity and minimum nonspecific binding,” said Dian Er Chen, principal investigator, proteomics R&D. “The non-specific binding of the depletion system was evaluated by spiking the system with varying quantities of nonhuman proteins into sample plasma.”

Furthermore, Chen added that this depletion technology is significant because it allows for the enrichment and detection of low-abundant proteins, the category where most protein biomarkers reside. “Further development of this technology could lead to a screening system for early protein biomarkers of common diseases.”

TIRF Technologies discovers peptide and peptoid ligands for bioassays designed for the detection of bioterrorist agents and markers of various diseases. “Our technology, which is already on the market, is proficient at reading biomolecular interactions,” said Alexander Asanov, Ph.D., president and CEO. The technology is being utilized by many industries to perform sighted (nonrandom) screening for interactions between potential ligands in a peptide library.

“If there’s an interaction, we know it within seconds or minutes, in contrast to several hours or days typical for traditional technologies,” said Dr. Asanov. “This technology has been successfully used in the discovery of aptamers made of DNA oligomers, peptides, and peptoids.” 

A microarray of reagentless peptide-based FRET assays printed on the surface of a TIRF-EC slide from TIRF Technologies.

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