Why protein chemist chose phosphorus for protein bioconjugation?

In the last two decades, phosphorus-mediated chemoselective ligation reactions acquired the “gold” status for in vivo labeling of biomolecules. However, some drawbacks of phosphines, such as directing non-canonical amino acids (e.g. azides) as their reaction partners limits the scope of these reactions. Thus, for chemical approaches, targeting canonical amino acids on proteins as targets for site-specific conjugation are of prime importance. Indeed, protein chemists developed several methods using canonical amino acids as selective conjugation sites. Continue reading

Conjugates of Vancomycin and Cell-penetrating Peptides – New Weapons in the Armoury against Drug Resistant Bacteria

Staying one step ahead in the arms race against antibiotic resistant pathogenic bacteria is an ongoing challenge to the ingenuity of medicinal chemists. Multidrug-resistance has become a menacing threat to the antibiotic armoury used by clinicians to treat nosocomial and community-acquired bacterial infections. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most notorious of such hospital-acquired pathogens. Until recently, the glycopeptide antibiotic vancomycin (Van) was available as a last resort, to effectively treat patients suffering Continue reading

Bioactive peptides from food protein degradation: Legume peptides

Animal and plant proteins, upon in vitro or in vivo digestion, have not only a nutritional role but are a rich source of bioactive peptides initially encrypted in the native protein sequences. The activities of these peptides range from antioxidant, antihypertensive or anti-obesity to antimicrobial or antitumoral. To illustrate the diversity of food-derived active peptides and their possible benefits for health, in this short report I have compiled a few recent examples of peptides isolated Continue reading

Nature’s Shotgun Proteomics

The mammalian immune system, as part of its response to a viral infection, does something akin to a shotgun proteomics experiment. Viral proteins are digested, and the resulting peptides are presented—as a mixture—in a form that can be recognised by circulating T cells. In this article, I follow the ‘experiment’ through its various stages, and discover that it is possible for a real-life proteomics experiment to pick up from where the in vivo processes left Continue reading

Thanatin – an Insect-derived Antimicrobial Peptide Active against Pathogenic Gram-negative Bacteria

Swiss researchers have recently revealed the mechanism by which the insect-derived antimicrobial peptide thanatin targets the intermembrane protein complex required for lipopolysaccharide (LPS) transport in Escherichia coli. Employing a series of elegant techniques directed at increasing levels of magnification and ultimately, structural determination by NMR, these researchers show how thanatin interferes with assembly of the seven-member macromolecular protein complex which forms a molecular bridge supporting ATP-driven transport of LPS from the inner membrane to the Continue reading

Peptide vaccines: the future of immunotherapy?

It is widely accepted that vaccines are valuable preparations for prevention against life-threatening diseases such as polio, measles and smallpox and their utilization led to control and/or eradication of aforementioned infectious diseases. Common drawbacks in classical vaccine formulations led to the development of less allergenic and more specific peptide vaccines that usually consist of 20-30 amino acids and an external adjuvant to enhance immunogenicity of peptide epitopes, which are normally weak antigens and could therefore Continue reading

Targeted protein degradation as a new paradigm in drug discovery. Is there a role for peptides?

Despite the large number of new, therapeutically relevant proteins discovered in recent years, classical drug discovery strategies have not been particularly successful in finding suitable small-molecule modulators. Targeted protein degradation has raised considerable interest from pharmaceutical/biotech companies and academic groups as a novel paradigm in drug discovery. Two main strategies to generate protein degraders have been identified: 1) Protein-targeting chimeric molecules (PROTACs), and 2) Hydrophobic tagging (HyT). In the first case, multifunctional hybrid molecules containing Continue reading

Small Proteins, Big Data

The possibility that a subset of biological molecules has been overlooked, and is waiting to be discovered, is always intriguing. For small proteins (proteins of around 100 amino acid residues or fewer) there is evidence to suggest that this is indeed the case. In this article, I examine the defining characteristics of small proteins and survey the methods by which such proteins are analysed. The graphical abstract depicts NMR models of human sarcolipin (image of Continue reading

Inhibition of Amyloidogenesis by Synthetic Enantiomeric Peptides

A synthetic peptide composed of alternating L- and D-amino acid residues has been recently shown to inhibit aggregation and reduce toxic effects in neuroblastoma cells, of the beta-amyloid peptide, Aβ, implicated in Alzheimer’s disease. In contrast, a “twin” peptide with the same sequence, but with all L-amino acid residues, had no inhibitory effect on amyloidogenesis or toxicity of Aβ. For more please download PDF file. Contributed by Susan J. Tzotzos Susan Tzotzos works for the Continue reading

New enzymatic approaches for the generation of peptide and protein conjugates

Enzymatic conjugation of peptides and their analogues to other peptides or proteins is considered to be an exciting field in protein chemistry. Besides Sortase A, Butelase and Transglutaminase, the field offers attractive possibilities with respect to its broad spectrum and simplicity. Nevertheless, certain issues such as the length of the peptide tag, sophisticated purification protocols to separate enzymes from the product and high amounts of enzymes used limit the scope of these approaches. In this Continue reading