Registration of Custom Peptides in a Lab Informatics Platform Streamlines Tracking
Peptides are possibly the “Goldilocks” of therapeutic molecular entities – not too big, and not too small. And with their attractive pharmacological profiles including excellent specificity, safety, tolerability, and efficacy, they are “just right” to provide a useful jumping off point for the design of novel therapeutic agents.
The Increasing Market for Peptide Therapeutics
In 2015 there were more than 60 FDA-approved peptide therapeutics on the market, with 140 more being evaluated in clinical trials, and greater than 500 in pre-clinical development.[i] In 2014, the peptide therapeutics market was valued at US$ 16,000.0 Mn and revenue is expected to expand at a CAGR of 10.3% over 2015-2025.[ii]
This flurry of custom peptide synthesis is generating an increasing volume of experimental data that needs to be captured, stored, reported on, and made securely sharable. Central to this are the structures of the novel peptides which must be efficiently represented in a unique, unambiguous, and chemically intelligent way so researchers can keep track of their custom peptides and can assign corporate IDs for use in inventory and assay systems.
Requirements for a Peptide Registration System
In other words, peptide chemists need a registration system tailored to their specific requirements – in the same way that small molecule chemists track their compounds in a chemical registration system.
Linear peptides have a well-developed formalism to represent their constituent strings of amino acids, using the standard IUPAC one- and three-letter abbreviations[iii] (e.g. Leu-enkephalin can be represented as Tyr‑Gly-Gly-Phe-Leu or Y-G-G-F-L). Modern chemical sketchers provide simple tools for peptide chemists to input these linear amino acid strings by typing or picking from a palette, and the sketchers have chemical intelligence built in, so that each amino acid residue has its full chemical connectivity and stereochemistry available for expansion, display and modification as needed.
Core’s Peptide Registration app uses the ChemAxon chemical sketcher to draw or load peptides. The sketcher comes pre-loaded with all the common amino acid building blocks as well as protecting groups, linkers, and attachments to make drawing peptides quick and easy. The ChemAxon sketcher can also read structure files created in ChemDraw.
Modifying Simple Linear Peptide Chains
One of the challenges in peptide chemistry is how to stabilize novel, potential peptide therapeutic entities to protect them from things like unwanted metabolism or aggregation, and a variety of techniques are available. These include using unnatural D-amino acids and beta-amino acids, inserting internal cyclization bonds (between terminal amino acids and cysteine/cysteine bridges and lactam rings), N‑methylation, addition of terminal and side chain protecting groups, and insertion of other chemically modified entities.
Each of these modifications to a simple linear peptide chain needs to be represented structurally, and Core’s Peptide Registration app exploits the power and simplicity of the ChemAxon chemical sketcher to handle all these variations. Intramolecular cyclizations are indicated by simple additions to the linear representation to indicate the cyclization points, end caps and protecting groups are available in the Abbreviations file for ready addition to a peptide, and custom residues can be drawn, named and stored with full connectivity, stereochemistry, and attachment points for sharing and reuse in other peptides.
Checking for Novelty in Custom Peptide Synthesis
With all these tools at their disposal, researchers involved in peptide synthesis can quickly and accurately draw what they have developed during peptide synthesis, secure in the knowledge that the full and explicit chemical structure is available from the shorthand sequence.
Having drawn or input the custom peptide structure, the chemist can then check its novelty using the Peptide Registration app. The app compares the input structure against the existing registry file, and if the structure is novel, it is assigned a new, unique registration number. If there is a match, the existing compound is displayed, and the chemist can either amend the input structure, or assign it a new lot or batch number of the existing compound. On input of the amino acid string, the full structure is computed and cleaned up, and associated properties such as molecular formula and molecular weight are calculated.
Tools for Tracking Custom Peptides in a Laboratory Information Management System (LIMS)
There are also tools in the Peptide Registration app to allow loading and bulk registration of sets of compounds, which can be submitted as SDfiles / SDFs containing the corresponding amino acid strings.
Once a peptide is registered, a chemist can create a lot of the material and add the specifics of the particular lot, such as associated projects and salt forms and equivalents. And if required, container records associated with the lot can be created and added to the inventory file. Mandatory fields and required formats can all be built in to the registration system using simple configuration tools to ensure adherence to corporate business rules and standards.
The peptide registry file is chemically searchable to locate specific compounds (exact search) and also to search for peptides containing a particular substructure (substructure or similarity search), or partial sequence of amino acids using advanced sequence search tools such as contains/does not contain/starts with/ends with.
A Powerful Laboratory Informatics System for Peptide Synthesis and Therapeutic Discovery
The Peptide Registration app equips peptide chemists with a powerful yet easy-to-use and intuitive system for drawing, registering and storing peptides, including those with novel custom residues, so that the novel entities can be identified and tracked as they move through inventory and into bioassay and other test systems. The app runs in conjunction with the Core LIMS to support peptide synthesis in a seamless manner, all on the Platform for Science, to support laboratory informatics across the R&D organization.
[i] Drug Discovery Today, Vol. 20, Issue 1, January 2015, pp. 122-128.
[iii] Nomenclature and Symbolism for Amino Acids and Peptides (Recommendations 1983), Eur.J.Biochem., Vol. 138, pp.9-37 (1984)