Current medicinal chemistry · 2026
Synthetic AtMP2 from Anabas testudineus: Comprehensive ADMET and In Vivo Toxicity Assessment to Enable Future Therapeutic Development.
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Mohd Noordin Muhammad Akram, Najm Ahmed Abdulkareem, Huei Wern Lim, Eziwar Dyari Herryawan Ryadi, Law Douglas, Fazry Shazrul
Аннотация
BACKGROUND/OBJECTIVES: Breast cancer remains one of the common causes of cancer mortality globally, and the development of safe and selective anticancer agents remains an important research priority. AtMP2, a synthetic peptide derived from the mucus of climbing perch (Anabas testudineus), has previously demonstrated anticancer activity against breast cancer cell lines. However, its pharmacokinetic properties and in vivo safety profile have not been comprehensively evaluated. Therefore, this study aimed to investigate the ADMET-related characteristics and preliminary in vivo safety of AtMP2 using integrated in silico, in vitro, and in vivo approaches.
METHODS: The ADMET profile of AtMP2 was evaluated using in silico prediction (ADMETlab 2.0) and in vitro assays examining 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 assessed. Acute and sub-acute toxicity studies were conducted in female BALB/c mice (n = 5 per group) following intravenous administration.
RESULTS: AtMP2 was hydrophilic (logD = -0.86 ± 0.3), showed a high plasma unbound fraction (65.9%) and microsomal unbound fraction (91.4%), moderate metabolic stability (t1/2 = 136.53 ± 12.6 min), and moderate intrinsic clearance (10.86 ± 0.2 mL/min/kg). Permeability studies demonstrated measurable transport with moderate efflux via the P-glycoprotein efflux pump (efflux ratio = 2.43). AtMP2 was not cytotoxic to MDCK-MDR1 cells, retained antibacterial activity, and did not cause mortality, abnormal behaviour, significant body-weight changes, or histological evidence of organ damage at doses up to 15 mg/kg in mice.
DISCUSSION/CONCLUSION: Collectively, these findings suggest that AtMP2 possesses encouraging preliminary ADMET-related and short-term tolerability characteristics for an early-stage peptide lead. The present study provides an initial preclinical assessment of AtMP2 and supports its continued investigation as a potential peptide-based therapeutic candidate. Nevertheless, further pharmacokinetic, biochemical safety, long-term tolerability, and efficacy studies remain necessary.
METHODS: The ADMET profile of AtMP2 was evaluated using in silico prediction (ADMETlab 2.0) and in vitro assays examining 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 assessed. Acute and sub-acute toxicity studies were conducted in female BALB/c mice (n = 5 per group) following intravenous administration.
RESULTS: AtMP2 was hydrophilic (logD = -0.86 ± 0.3), showed a high plasma unbound fraction (65.9%) and microsomal unbound fraction (91.4%), moderate metabolic stability (t1/2 = 136.53 ± 12.6 min), and moderate intrinsic clearance (10.86 ± 0.2 mL/min/kg). Permeability studies demonstrated measurable transport with moderate efflux via the P-glycoprotein efflux pump (efflux ratio = 2.43). AtMP2 was not cytotoxic to MDCK-MDR1 cells, retained antibacterial activity, and did not cause mortality, abnormal behaviour, significant body-weight changes, or histological evidence of organ damage at doses up to 15 mg/kg in mice.
DISCUSSION/CONCLUSION: Collectively, these findings suggest that AtMP2 possesses encouraging preliminary ADMET-related and short-term tolerability characteristics for an early-stage peptide lead. The present study provides an initial preclinical assessment of AtMP2 and supports its continued investigation as a potential peptide-based therapeutic candidate. Nevertheless, further pharmacokinetic, biochemical safety, long-term tolerability, and efficacy studies remain necessary.