Synthetic AtMP2 peptide demonstrates favorable ADMET and in vivo safety profile up to 15 mg/kg in mice

Despite advancements, breast cancer remains a leading cause of cancer mortality, necessitating the discovery of safe and selective anticancer agents. Conventional therapies often face challenges like systemic toxicity, poor selectivity, and drug resistance. AtMP2, a peptide derived from climbing perch mucus, previously showed anticancer activity against breast cancer cell lines. However, a comprehensive evaluation of its pharmacokinetic properties (ADMET) and in vivo safety profile was lacking, which this study aimed to address to enable future therapeutic development.

Researchers evaluated the ADMET profile of AtMP2 using integrated in silico (ADMETlab 2.0), in vitro, and in vivo approaches. In vitro assays assessed lipophilicity, plasma and microsomal protein binding, metabolic stability in human liver microsomes, and bidirectional permeability in MDCK and MDCK-MDR1 cell lines. Cytotoxicity against mammalian cells and antibacterial activity were also examined. Acute and sub-acute toxicity studies were conducted in female BALB/c mice (n = 5 per group) following intravenous administration of AtMP2 at doses up to 15 mg/kg. Primary endpoints included mortality, abnormal behavior, body-weight changes, and histological evidence of organ damage.

AtMP2 exhibited a hydrophilic nature with a logD of -0.86 ± 0.3, indicating good aqueous solubility. It demonstrated a high plasma unbound fraction of 65.9% and an even higher microsomal unbound fraction of 91.4%, suggesting good bioavailability and reduced drug-drug interaction potential. The peptide showed moderate metabolic stability with a half-life (t1/2) of 136.53 ± 12.6 min and moderate intrinsic clearance of 10.86 ± 0.2 mL/min/kg. Permeability studies revealed measurable transport across cell membranes, with moderate efflux mediated by the P-glycoprotein efflux pump (efflux ratio = 2.43). Importantly, AtMP2 was not cytotoxic to MDCK-MDR1 cells, retained its antibacterial activity, and crucially, demonstrated an excellent safety profile in vivo. > No mortality, abnormal behavior, significant body-weight changes, or histological evidence of organ damage were observed in mice treated with AtMP2 at doses up to 15 mg/kg.