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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.
  • Crystal Structure of D-peptides binding to their target. Two D-peptides (blue surface and cartoon) bound to their trimeric target (gray surface). A third D-peptide is behind the target and is not visible.

    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 also 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.

     

    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. 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 process.

    Targets: Access to sterically restricted targets not amenable to biologics and protein-protein interfaces that are typically difficult for small molecules to disrupt.

    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.

    Why Navigen?

    • 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 has assembled a team of outstanding scientists with extensive experience in D-peptide discovery and optimization. Our team is committed to establishing Navigen as the industry leader in bringing important new D-peptide therapies forward.
  • Navigen's D-Peptide Discovery Process

    Navigen 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.
  • Mirror-image phage display. The target of interest is synthesized using D-amino acids and folded into the mirror image structure of the natural L-target. This D-target is then used as bait in successive rounds of phage display to identify an L-amino acid peptide that binds to the D-target with high affinity and specificity. Reversing the arrangement and synthesizing the binding peptide using D-amino acids yields the mirror-image interaction, a synthetic D-peptide binding to the natural L-target.
  • 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 expanded our original technology platform and now has one program in IND-enabling studies, one program in advanced lead optimization, and one program in hit validation (CPT31 for HIV treatment and prevention, CR32T for RSV treatment and prevention, and anti-TNFα hits, respectively). We expect to continue to apply our platform to a diverse set of 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.