(C-88) Synthetic growth factor mimicking materials platforms from in silico design to in vivo efficacy

Introduction::
Self-assembling peptide hydrogels (SAPH) are a class of injectable scaffolds that present a paradigm in drug development and biomaterials ^{1, 2, 3}. Facile self-assembly of monomeric/ multimeric constituents result in high epitope presentation of biological signals. Persistent signaling, in situ bolus delivery and demonstrable modification to actuate specific biological responses allowing development of novel classes of biomaterials that behave as scaffolds and drugs. Building on initial work in cholesterol metabolism and presentation of a PCSK-9 inhibitory peptide on SAP scaffolds, we have expanded our milieu of applications and a significantly deeper understanding of in silico peptide design to in vivo efficacy studies. This platform has been investigated and will be discussed for:




Tissue regeneration/ revascularization




Drug delivery




IGF driven diabetic fracture healing




COVID therapeutics




We additionally will describe entrepreneurship and innovation helping bridge the gap between academia, industry and clinical medicine.




Materials and Methods::
Our work in novel peptide-drug-biomaterial developments begins with rationalized peptide design based on canonical receptor-ligand interactions. Candidate peptides are design for improved stability using macrocyclization and D-peptides. Peptides are synthesized and characterized for supramolecular self-assembly of nM-mM aqueous formulated hydrogels in 1x PBS / saline. Peptides are then tested for in vitro and in vivo safety and efficacy using a number of mammalian cell and animal models, Figure 1.




Results, Conclusions, and Discussions::
Results:




We have designed a number of peptides biomaterial drugs and herein describe a vignette of key results:




1) SARS-CoV-2 binding peptide:




i) Computational strategy: ACE-2 mimic




ii) In vitro efficacy: vs pseudovirus & livevirus (IC50 nM)




iii) In vivo efficacy: ongoing in hamster model




2) IGF mimicry:




i) Computational strategy: IGF-1c mimic derived from IGF-IGFR interaction/ stability of binding




ii) In vitro efficacy: phos-AKT, looking for phos IGFR




iii) In vivo efficacy: ongoing muscle regeneration using these and VEGF mimetic hydrogels.




3) MCP-1 binding peptide:




i) Computational strategy: CCR-2 mimic derived from binding pocket analysis of CCR-2-MCP-1




ii) In vitro efficacy: ELISA blocking of MCP-1 Ab binding




iii) In vivo efficacy: inflammation model next




4) VEGF binding peptide:




i) Computational strategy: novel “QK” VEGF-A/VEGF-15 mimics; receptor dimerization using self-assembly




ii) In vitro efficacy: MST binding to VEGFR1/2




iii) In vivo efficacy: pulp regeneration









Discussion:




High resolution structures of protein interactions have given insight into mimicking domains that can recapitulate signaling. We have harnessed this, along with advances in supercomputing and peptide synthesis, to create a robust workflow for (peptide) biomaterial design.




These peptides self-assemble and remarkable, reliably, display their cargo – owing to the stability and self-assembly of the unit assembling domain.




In vitro and in vivo these rationally designed materials have shown promise in disease mitigation (SARS-CoV-2) to tissue regeneration (VEGF-mimicry).









Conclusions:




The research vignettes presented showcase a biomaterials that has a milieu of effective function based on computationally design moieties and binding. We have shown efficacy against viral targets and promotion of angiogenesis. This platform is amenable for a multitude of in vivo tissue engineering and drug delivery applications owing to its thixotropic (injectable), biodegradable bolus, aqueous formulation that can be exploited for a number of tissue engineering applications.




Acknowledgements (Optional): :
Acknowledgements:




Acknowledgements to recent funding: NIDCR R01DE031812 (PI), NIDCR R01DE029321 (Co-I), NEI R15EY029504 (PI), NIAMS R21AR077835 (PI), NCATS UL1TR003017 (PI), NSF IIP 2041092 (PI), NSF STTR 2032392 (Founder/ Pres.).









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