The Multifunctional Therapeutic Potential of Dermaseptin S4 and Its Analogs: A Comprehensive Review of Structure, Mechanisms, and Biomedical Applications

Introduction Driven by the global crisis of multidrug resistance and the critical need for multifunctional therapeutics, this review systematically evaluates Dermaseptin S4 (DS4)—a potent antimicrobial peptide derived from Phyllomedusa frogs—and its engineered derivatives. It delineates their structural biology, biophysical mechanisms of action, and structure-activity relationships (SAR) to guide future peptide design. Methods A systematic literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar for peer-reviewed studies focusing on the characterization and pharmacological activities of DS4 and its analogs. Results Native DS4 is a 28-residue polycationic peptide that adopts an amphipathic alpha-helix upon membrane interaction, disrupting bilayers via "carpet" and "barrel-stave" models. Engineered analogs (e.g., K4K20-S4 and acyl-derivatives) exhibit potent, broad-spectrum activity against critical multidrug-resistant clinical isolates, including MRSA and Klebsiella pneumoniae , alongside robust antifungal and antiparasitic efficacy. Furthermore, rational structural modifications successfully optimize its selective anticancer toxicity against malignant cell lines (such as SW620 and HeLa) via membrane lysis and regulated cell death pathways, while successfully minimizing undesirable hemolytic toxicity. Conclusion Delineating the SAR of DS4 provides a robust framework for designing optimized, safer, and highly selective peptide-based therapeutics for clinical translation.