Gyros Protein Technologies recently published four review articles on Genetic Engineering & Biotechnology News' content forum GEN BioPerspectives. Learn more about how our peptide synthesis platforms have been applied in research and development of biotherapeutics.
There has been a recent revival in interest in peptide therapeutic development, with five of the top-selling drugs being peptides or proteins (Enbrel, Remicade, Humira, Avastin, MabThera) and many more currently in clinical trials . Among their many advantages, peptide therapies provide high levels of receptor recognition that reduce toxicity profiles and drug-drug interaction potential . However, in some cases these therapies have disadvantages, such as low membrane permeability, easy degradation by proteases, and unspecific proteolysis that limit duration of action and oral bioavailability. Researchers are working on a variety of solutions to overcome these roadblocks, including structural modifications such as D-amino acids substitutions, modifying peptide terminals, covalent attachment of fatty acids or PEG, and peptide cyclization.
The fight to improve cancer therapy has included the development of ligand-mediated active targeting to guide anticancer drug cargos more directly to their specific targets. Tumor-associated macrophages (TAMs), found in the tumor microenvironment, mostly express an anti-inflammatory “M2” phenotype and contribute to tumor progression, angiogenesis, and metastasis. Researchers at University of Washington have developed and further refined peptide-targeted drug delivery aimed at selectively depleting TAMs. To do this, they have fine-tuned the sequence of a targeting peptide, M2pep, designed to deliver a conjugated drug cargo directly to the M2 macrophage. Modifications to the peptide sequence improved serum stability and also increased M2 macrophage binding activity.
Protein misfolding can lead to abnormal conformations, fibril formation, and aggregation that cause severe conditions such as amyotrophic lateral sclerosis (ALS), prion diseases, and Alzheimer’s disease. Wild-type and mutant transthyretin (TTR), for example, can misfold and deposit in tissues to cause amyloid disease. Small-molecule drugs aimed at this disease act as pharmacological chaperones that inhibit TTR misfolding by stabilizing native tetrametric TTR, but have severe side effects or must be administered at high concentrations. Natalie Galant and Antoinette Bugyei-Twum, University of Toronto, together with Rishi Rakhit, Stanford University, and other researchers have tested a novel approach to solving this problem. They harnessed the specificity of antibodies using a “structurally guided” design to target a sequence that is buried deep in natively folded TTR, but exposed in misfolded and monomeric forms. The result is a diagnostic and potential therapeutic antibody that functions at substoichiometric concentrations to inhibit amyloid formation.
Macromolecules such as peptides, proteins and siRNAs show great promise as therapeutic agents in precision medicine, but their large size complicates delivery into the cytoplasm or nucleus. Adding peptide/protein transduction domains (PTDs) or cell-penetrating peptides (CPPs) can promote cellular uptake of macromolecules through endocytosis, but escape from endosomes into the cytoplasm remains a challenge. Using an elegantly simple complementation assay, Peter Lönn and his colleagues at UCSD School of Medicine, La Jolla, USA have investigated how covalent attachment of the hydrophobic motifs of designer peptides—endosomal escape domains (EEDs)—to a PTD/CPP can overcome the challenge of ensuring efficient release of a macromolecular drug from the endosome into the cytoplasm with minimum cytotoxicity.