Synthesis and pharmacological evaluation of a novel synthetic peptide CWHTH based on the Styela clava-derived natural peptide LWHTH with improved antioxidant, hepatoprotective and angiotensin converting enzyme inhibitory activities

LWHTH (Leu-Trp-His-Thr-His) is an antioxidant pentapeptide isolated from Styela clava tissue. Based on LWHTH, we designed and synthesized a series of novel peptides using the alanine scanning technique and determined the pharmacological activities of these derivatives. Among the ten newly synthesized LWHTH analogs, peptide CWHTH was identified as the most potent compound with prominent antioxidant activity. CWHTH not only showed the ability to scavenge several biologically important radicals, protected cells from H2O2 or APAP-induced damage by activating the PI3K/Akt and suppressing the JNK/c-Jun pathways, but also exerted strong in vivo hepatoprotective effects in an APAP-induced liver injury model in mice. Moreover, it was demonstrated that CWHTH possesses potent angiotensin converting enzyme (ACE) inhibitory activity and high stability against gastrointestinal proteases. In summary, CWHTH is a promising antioxidant peptide worthy of further investigation as a potential hepatoprotective and antihypertensive agent.