Associate Professor New Jersey Institute of Technology Newark, New Jersey, United States
Introduction: Monomeric ‘self-assembling peptides’ (SAP’s) assemble into multimeric β-sheet nanofibers in situ through interaction of a central self-assembling domain. The self-assembling domains are flanked by terminal domains of growth factors (GF) ‘mimics’ that are designed to target specific molecular, cellular or microbial receptors, or antimicrobial termini for wound healing and dental applications. Multimeric peptide assemblies are strain-resistant, are both cytocompatible in vitro and biocompatible in vivo, stable at a range of temperatures and are compatible for administration via numerous modalities.
Materials and
Methods: Our therapeutic peptide-focused lab adopts a comprehensive workflow to drug discovery, including (i) in silico peptide design with molecular simulation of binding their molecular targets, (ii) in-house solid phase synthesis of peptide, (iii) in vitro validation of peptide efficacy and proof-of-concept, and (iv) in vivo testing of promising peptide candidates in animal models of disease, malformation and injury.
Results, Conclusions, and Discussions:
Results: Utilizing this approach, hawse have designed and screened SAP’s with growth factor ‘mimics’. For example, we designed self-assembling hydrogels with terminal mimics based on the receptor binding domain of insulin-like growth factor-1 (IGF1). Hydrogels bind IGF receptors in a dose-dependent fashion, activate pro-angiogenic Akt signaling and facilitate formation of collagenated angiogenic microtubules in vitro. Furthermore, infiltrated hydrogels are stable for weeks-months long time period. When administered to an animal model of Hind Limb Ischemia (HLI), administration of IGF1 hydrogels to ischemic limbs significantly rescued deteriorating tissue and restored limb mobility by treadmill assay. We have developed another SAP with terminal cationic domains that possess wide spectrum anti-microbial activity, projected for wound healing and dental root canals applications. To meet these unmet needs for a product that maintains a microbe-free environment, promote infiltrating angiogenesis and tissue growth and/or preserved dental tissue, we show very efficient antimicrobial activity against various bacterial and fungal strains. Another antiviral SAP self-assembles into fibrils that maintain enhanced binding to viral protein (including COVID19, and its mutants). Our SAPs are cytocompatible and safe in rodents, injectable, and biodegrades in vivo. Discussions: The rational in silico design of alternative terminal domains enables the targeting of a wide range of molecular targets, and therefore holds potential across a number of therapeutic applications. This is encapsulated in the Figure below.
Conclusions: We conclude that enhanced targeting and long-term stability and enhanced half-life of our SAP/GF mimicry implants may improve the efficacy and safety of future GF mimic regenerative therapeutics. Furthermore, we are continuing to screen our antimicrobial SAPs against additional bacterial and fungal strains to realize its full therapeutic potential. Finally, we are expanding our platform to other clinical applications, including peripheral artery disease and surgical procedures.
