Peptides offer attractive opportunities for drug design as they combine the stability of traditional small-molecule therapeutics with the specificity and potency of larger antibody-based drugs. The larger surface area and increased number of atomic interactions from peptides enable both better affinity and specificity for targets like protein-protein interfaces that have traditionally been considered "undruggable" [1]. However, due to their general lack of membrane permeability, peptide therapeutics are currently limited to extracellular targets, and require non-oral routes of administration. This limits their use in the developing world and in chronic conditions.
We previously developed computational tools defining biophysical rules for precise, de novo design of hyperstable peptides and macrocycles made of canonical and non-canonical amino acids [2, 3]. Bhardwaj lab is focused on extending these structure-guided design methods and integrating them with high-throughput chemical synthesis methods to achieve functional applications in two broad areas:
De novo peptide DESIGN for cell permeability, oral bioavailability and blood-brain barrier traversal
The ability to custom design peptides with membrane permeability encoded in their structure is critical for enhancing the versatility of peptide-based therapeutics. Peptides with intrinsic membrane permeability can access intracellular drug targets, can be orally delivered via translocation across intestinal epithelial cells, and can penetrate the BBB by traversing brain microvascular endothelial cells. Previous efforts focused on naturally-occurring cell-permeable peptides have shown limited applicability among peptides with different shapes and sizes.
Bhardwaj Lab is developing a general ‘rulebook’ for custom design of membrane-permeable peptides by taking an iterative structure-oriented approach: each feature hypothesized to enhance membrane permeability is systematically tested by design of ordered peptides enriched for that structural feature and their experimental evaluation via large-scale in vitro and in vivo permeability assays.
High-throughput design and screening of targeted peptide therapeutics
Small-molecules and antibodies have shown limited ability to target intracellular therapeutic proteins; small-molecules show poor affinity and selectivity against larger protein-protein interactions while antibodies lack membrane permeability. In principle, peptide therapeutics can be designed to have cell permeability and superior selectivity by extending the interaction surface beyond the footprint of small molecules. However, current methods for developing peptide-based therapeutics sample limited structural diversity and have low success rates. There is a pressing need to develop computational methods for accurately designing peptides that can bind to any arbitrary pharmacological target.
We have previously developed tools for computational design of hyperstable, protease-resistant nonnative peptide structures with unprecedented precision. Bhardwaj Lab is now developing an integrated computational-combinatorial platform for precise design of peptides in binding-competent conformations that complement the target of interest. Ongoing focus of our computational-combinatorial platform is to develop new peptides to counter the growing threat of drug resistance, chronic pain and neurodegenerative disorders.
