TechnologyUnlocking the Power of D-peptides
- Navigen is bringing a new level of innovation and insight to peptide therapeutics based on the unique properties of D-peptides and our extensive experience in drug design and engineering.
Peptides are short chains of amino acids that often act as highly selective and efficient signaling molecules in the body. They offer many advantages in pharmaceutical applications. Their high specificity and affinity translate into advantageous safety, tolerability, and efficacy profiles compared to traditional small molecules.
Naturally occurring peptides are almost exclusively composed of L-amino acids (L-peptides). In contrast, D-peptides, which are synthetically produced and not typically found in the body, are composed of D-amino acids, which are the mirror image of L-amino acids. Naturally occurring peptides have intrinsic weaknesses, including poor metabolic stability and a short circulating plasma half-life, that can diminish their usefulness as pharmaceuticals. Naturally occurring peptides frequently induce an immune response that leads to anti-drug antibody formation that can further limit their effectiveness.
The body’s natural mechanisms for recognizing and metabolizing peptides are designed to target L-peptides, not D-peptides. Thus, D-peptides are not readily degraded and are largely non-immunogenic. With these and other advantages, D-peptides have significant potential to be a new class of highly effective and safe therapies.
D-peptides Combine the Advantages of Biologics and Small Molecules Both in Terms of Their Properties and the Drug Discovery ProcessTargets: Access to sterically restricted targets not amenable to biologics and protein-protein interfaces that are typically difficult for small molecules to disrt.
Time to Clinical Candidate: Antibody-like lead identification without required humanization or cell line development.
Chemical Synthesis: Antibody-like potency with the benefits of chemical synthesis, including modularity.
Safety: Lack of significant off-target side effects and minimal immunogenicity enable safe chronic dosing.
The Time Has Arrived for D-Peptide Therapeutics
The potential of D-peptide-based therapeutics has been known for some time. However, several limitations have prevented broad application of this technology.Why Now?
- D-peptide discovery requires that the target of interest be produced synthetically using D-amino acids (see mirror-image phage display below). Historically, due to the size constraints of synthetic peptide production, D-peptide screening was limited to relatively small targets. However, Navigen scientists are experts at large protein synthesis. In fact, during his doctoral work in the University of Utah laboratory of our close collaborator Dr. Michael Kay, one of Navigen’s scientists was instrumental in producing the largest synthetic proteins ever made at that time (Weinstock et al. PNAS. 2014;111:11679-11684).
- Cost of synthesis of identified D-peptide drug-leads is now comparable to L-peptides.
- 50+ years combined experience working with D-peptides .
- A leader in large target protein synthesis - capable of synthesizing most extracellular targets.
- Proprietary tools to ensure successful target synthesis.
- Diverse and proprietary peptide phage display libraries composed of 50B unique sequences, representing multiple peptide geometries.
- Optimized screening protocols.
- Custom-built bioinformatics suite to rapidly analyze screening data and identify hits.
- Expertise optimizing pharmaceutical properties.
Navigen's D-Peptide Discovery ProcessNavigen licensed technologies from the University of Utah, where a team of scientists (several of whom are now at Navigen) led by Dr. Michael Kay established that D-peptides can be engineered to potently inhibit entry of HIV into cells. The Kay lab and Navigen continue to work together to advance and broaden this technology.
- By using mirror-image phage display and custom tools that facilitate the discovery process, Navigen’s scientists rapidly screen our highly diverse proprietary phage libraries (>50 billion unique sequences) to identify peptides able to bind to therapeutically important targets. The selected peptides are then affinity matured and engineered to possess optimal properties (e.g., PK enhancement, localization to site of action).
- Navigen has built a world-class D-peptide discovery platform that we are leveraging to discover important new therapeutics with the special characteristics of D-peptides. Our lead compound is a D-peptide entry inhibitor for HIV, CPT31 for which we expect to initiate human studies in the first quarter 2020. We also have discovery programs for SIRPα and TNFα inhibitors as well as for two additional, undisclosed, targets.
- Our proprietary tools and expertise position Navigen to be the world leader in D-peptide drug development. We are building a robust pipeline of novel therapeutics targeting critical areas of unmet need and are also collaborating with companies interested in working with Navigen to create new D-peptides for targets of interest.