Peptides (or polypeptides) are chains of amino acids that help form the basis of proteins. Since there are so many possible sequences of the 20 known amino acids, peptides can have a plethora of functions. This characteristic of peptides allows them to become drugs with a wide range of applications. Along with this, peptide-based drugs generally have the highest success rate in clinical trials meaning they are more likely to become a drug than other alternatives - not including existing medicines.
Small peptides in particular have the advantages of small molecule drugs, like aspirin or stelara. But, they also have the benefits of large antibody therapies, such as Rituxan. This means that they can be both stable and potent unlike most drugs which sacrifice one for the other.
Naturally occurring peptides that may serve as reliable scaffolds, moreover, are very few. What is worse is that when a peptide is repurposed using a scaffold, it often fails to do the function it was meant to perform. The method described in the report, “Comprehensive computational design of ordered peptide macrocycles,” seeks to change these facts to make creating peptide-based drugs faster, cheaper and generally easier.
"In our paper," the researchers said, "we describe computational strategies for designing peptides that adopt diverse shapes with very high accuracy and for providing comprehensive coverage of the structures that can be formed by short peptides."
Along with explaining their method, the researchers highlighted the advantages of their approach:
The database of reliable and stable scaffolds that they compiled can provide a base for all other peptide-based drugs that are created from now on. Along with this, their designed scaffolds can be used as a beginning for custom peptides.
"We sampled the diverse landscape of shapes that peptides can form, as a guide for designing the next generation of drugs," the researchers noted.
In order to create these scaffolds, moreover, the researchers had to keep the geometry and the chemistry of the molecules in check. This proved difficult considering the properties of different amino acids. Some amino acids are hydrophobic, others are hydrophilic; some are acidic, and others are basic. These characteristics influence the primary shape of the peptide which in turn would influence the scaffold. A scaffold that does not fit the different amino acids will be structurally unsound so it would not work. Thus the researchers were careful to keep close attention to these factors which they described by generally fitting amino acids into 2 categories: D-amino acids and L-amino acids.
The D-amino acids, in particular, aid in the pharmaceutical feasibility of the peptides. The D-amino acids increased natural resistance to enzymes the function to hydrolyse (or break down) peptides. The D-amino acids also allow for a wider array of possible shapes of the peptide.
The next goal for the scientists is to develop computer-designed scaffolds that have the capability to permeate membranes in order to penetrate the cell which could kill unwanted cells or help normal cells depending upon the function of the peptides.