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Synthetic AtMP2 from Anabas testudineus: Comprehensive ADMET and In Vivo Toxicity Assessment to Enable Future
Muhammad Akram Mohd Noordin1, Ahmed Abdulkareem Najm2,3, Lim Huei Wern1
1Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor, Malaysia.
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.
Insights
This study assessed the preliminary safety and ADMET properties of AtMP2, a peptide with anticancer potential. AtMP2 showed favorable characteristics, suggesting it
Area of Science:
- Pharmacology and Toxicology
- Peptide Therapeutics
- Cancer Research
Background:
- Breast cancer is a leading cause of cancer mortality worldwide.
- Developing safe and selective anticancer agents is a critical research area.
- AtMP2, a synthetic peptide from climbing perch mucus, shows prior anticancer activity against breast cancer cells.
Purpose of the Study:
- To investigate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) characteristics of AtMP2.
- To evaluate the preliminary in vivo safety profile of AtMP2.
- To assess AtMP2's potential as a peptide-based therapeutic candidate.
Main Methods:
- In silico ADMET prediction using ADMETlab 2.0.
- In vitro assays for lipophilicity, protein binding, metabolic stability, and cell permeability.
- Cytotoxicity and antibacterial activity assessments.
- Acute and sub-acute toxicity studies in BALB/c mice.
Main Results:
- AtMP2 is hydrophilic with high plasma and microsomal unbound fractions.
- Moderate metabolic stability and intrinsic clearance were observed.
- No cytotoxicity to mammalian cells; retained antibacterial activity.
- No mortality or significant adverse effects in mice at doses up to 15 mg/kg.
Conclusions:
- AtMP2 exhibits promising preliminary ADMET and short-term safety profiles for an early-stage peptide.
- The study supports further investigation of AtMP2 as a potential therapeutic agent.
- Further pharmacokinetic, safety, and efficacy studies are warranted.
