Peptides Gain Traction in Drug Development - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

Peptides Gain Traction in Drug Development
Although representing a small part of overall drug development, peptides and related technologies to improve their production are making inroads.


Pharmaceutical Technology Europe
Volume 24, Issue 6

Approaches to peptide synthesis

Stapled peptides. One important collaboration in peptide drug development is between the biopharmaceutical company Aileron Therapeutics and Roche. In November 2011, Aileron expanded its collaboration with Roche for the discovery, development and commercialisation of stapledpeptide drugs. The potential $1.1billion drug development collaboration, launched in August 2010, encompasses up to five programmes with the initial two programmes focusing on oncology, and a third programme being launched to focus on inflammatory diseases.


Public–private partnerships in biomanufacturing
Stapled peptides use peptide-stabilisation technology to enhance potency and cell permeability of a drug to address pharmacological limitations of small molecules and existing biologics in intracellular protein–protein interactions. Although small molecules can penetrate cells, the large binding surfaces for intracellular protein–protein interactions often make small-molecule modulators ineffective. As cited previously, peptides cannot permeate cells so act extracellularly (1, 10). Stapled peptides seek to resolve this problem. Because many undruggable therapeutic targets include those protein–protein interactions, in which alpha-helices are required in lock-and-key-type mechanisms, an approach is to design alpha-helical peptides that have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target and modulate the biological pathway (1, 10). Aileron stabilises peptides by "stapling" them with hydrocarbon bonds into an alpha-helix. Once constrained in the alpha-helix structure, the peptides are protected from degradation by proteases. The stabilised alphahelical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2, 10).

Researchers at the New York Structural Biology Centre recently reported on high-resolution solution nuclear magnetic resonance techniques with dynamic lightscattering to characterise a family of hydrocarbon-stapled peptides with known inhibitory activity against HIV-1 capsid assembly to evaluate the various factors that modulate activity. The researchers reported that helical peptides share a common binding motif, but differ in charge, the length and position of the staple. The research showed that the peptides share a propensity to self associate into organised polymeric structures mediated predominantly by hydrophobic interactions between the olefinic chain and the aromatic side-chains from the peptide. The researchers also detailed the structural significance of the length and position of the staple and of olefinic bond isomerisation in stabilising the helical conformation of the peptides as potential factors influencing polymerisation (11).

Cyclic peptides. In April 2012, researchers at Carnegie Mellon University (Pennsylvania, USA) reported on their manufacturing method for producing a synthetic form of a cyclic peptide. Macrocyclic peptides with multiple disulphide crosslinkages, such as those produced by plants and those found in nonhuman primates, hold potential as drugs because of their broad biological activities and high chemical, thermal and enzymatic stability (12). Because of their intricate spatial arrangement and elaborate interstrand crosslinkages, some macrocyclic peptides are difficult to prepare in large quantities and high purity because of the nonselective nature of disulphide-bond formation (12).

In the current study, the Carnegie Mellon researchers focused on RTD-1, a cyclic peptide held together by three disulphide bonds. RTD-1 has a broad range of antibacterial, antifungal and antiviral capabilities, and has been shown to inhibit HIV from entering cells. The researchers created a mimic of RTD-1. While the outside of the mimic peptide maintained the same amino acids as the original, the researchers replaced the disulphide bonds at its centre with noncovalent Watson–Crick hydrogen bonds without significantly affecting the biological activity of the peptide. The researchers say the work provides a general strategy for engineering conformationally rigid, cyclic peptides without the need for disulphide-bond reinforcement (12).

They tested the efficacy of the mimic RTD-1 by mixing the peptide with Escheria coli, Listeria, Staphylococcus and Salmonella— bacteria that RTD-1 typically protects against. The mimic proved to be effective in killing each of the types of bacteria tested by the researchers, which included both gram-positive and gram-negative bacterial strains. Furthermore, the mimic peptide worked by binding to the bacteria's cell membrane, not its DNA or RNA, decreasing the probability that the bacteria could develop resistance to the peptide. The researchers plan to see if the mimic RTD-1 is effective against other types of pathogens, including antibiotic-resistant bacteria. They also plan to apply their method to manufacture mimics of other cyclic peptides.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
Which of the following business challenge poses the greatest threat to your company?
Building a sustainable pipeline of products
Attracting a skilled workforce
Obtaining/maintaining adequate financing
Regulatory compliance
Building a sustainable pipeline of products
26%
Attracting a skilled workforce
29%
Obtaining/maintaining adequate financing
14%
Regulatory compliance
31%
View Results
Eric Langer Outsourcing Outlook Eric LangerBiopharma Outsourcing Activities Update
Cynthia Challener, PhD Ingredients Insider Cynthia Challener, PhDAppropriate Process Design Critical for Commercial Manufacture of Highly Potent APIs
Jill Wechsler Regulatory Watch Jill Wechsler FDA and Manufacturers Seek a More Secure Drug Supply Chain
Sean Milmo European Regulatory WatchSean MilmoQuality by Design?Bridging the Gap between Concept and Implementation
Report: Pfizer Makes $101 Billion Offer to AstraZeneca
Medicare Payment Data Raises Questions About Drug Costs
FDA Wants You!
A New Strategy to Tackle Antibiotic Resistance
Drug-Diagnostic Development Stymied by Payer Concerns
Source: Pharmaceutical Technology Europe,
Click here