Abstract 2140 Advancing Cell-Penetrating Peptides (CPPs) in Drug Delivery: Synthesis and Characterization of Novel CPP SARS-CoV-2 Fluorophore Conjugates

Cell-penetrating peptides (CPPs) are 5-30 amino acid sequences with the ability to modify cell permeability and enhance the transport of biomolecules as well as small therapeutics. According to the CPP database, over 1700 sequences have been identified. Although CPPs have been investigated for various malignancies including viral infections, they suffer from serious drawbacks such as non-specificity, low stability, and suboptimal pharmacokinetics. These clinical limitations along with lack of sufficient in vivo studies are the reason why no CPP or composition containing CPPs has been approved by the Food and Drug Administration (FDA). Since viruses are master intracellular parasites, viral-origin CPPs have been investigated in silico for their potential as effective shuttling vectors for cargo transportation into cells and exhibiting bioactive properties. Understanding the significance of viral-derived CPPs in enhancing drug bioavailability by navigating the challenges of limited cellular uptake is crucial in advancing drug delivery strategies. It is also necessary to verify the in silico data and generate the pharmacokinetic profiles based on toxicity, tissue distribution, cell selectivity, solubility, stability, immunogenicity, and degradation using in vitro and in vivo studies. We are investigating sequences derived from the SARS-CoV-2 proteome that was recently mined for CPPs in silico for their pharmacokinetic properties. The performance of these peptide sequences will be compared to HIV-TAT, which is one of the most widely studied CPPs and a CPP of viral origin. This work highlights our efforts on the chemical synthesis of these peptides using solid phase peptide synthesis (SPPS) and their conjugation to fluorescent probes. Development of these CPP-Probe conjugates will enable collection of in vitro data and help create pharmacokinetic profiles.