Peptide‐Drug Conjugate with Statistically Designed Transcellular Peptide for Psoriasis‐Like Inflammation

Abstract

Peptide‐drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems, including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, we employ physicochemical criteria based on cell penetrating peptides (CPPs) to design transcellular peptides derived from an antimicrobial peptides (AMPs) library. Among those the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, we find that 6‐Paradol (PAR) exhibited inhibitory activity against phosphodiesterase 4 (PDE4), which can be utilized for an anti‐inflammatory PDC. The transcellular PDC (SDT7‐conjugated with PAR, named as TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular peptide‐drug conjugates (TDCs) as a promising approach for the treatment of inflammatory skin disorders.This article is protected by copyright. All rights reserved