Structure-activity relationship study of the tumour-targeting peptide A20FMDV2 via modification of Lys16, Leu13, and
Kuo-Yuan Hung1, Paul W R Harris2, Ami Desai3
1School of Biological Sciences, The University of Auckland, 3a Symonds Street, Auckland Central 1010, New Zealand.
Abstract:
The 20-residue linear peptide A20FMDV2 has been shown to exhibit high selectivity and affinity for the tumour-related αvβ6 integrin and has potential as a vector for therapeutic drugs. However, it exhibits poor half-life in plasma in part due to its high susceptibility to serum proteases. In this study fourteen A20FMDV2 analogues incorporating non-proteinogenic substitutes of the native Lys16 and Leu13 residues and six A20FMDV2 analogues containing modified N- and C-termini were synthesised to increase the half-life and activity of A20FMDV2. The analogues incorporating modified terminal motifs of A20FMDV2 were found to strongly bind to the αvβ6 integrin and were subsequently functionalized with the diethylenetriaminepentaacetic acid chelating agent to facilitate coupling with radioactive indium-111 for human plasma stability and in vivo biodistribution studies. A20FMDV2 peptide variants incorporating an N-terminal d-Asn and C-terminal d-Thr exhibited improved relative activity in vitro and were less susceptible to plasma degradation.
Insights
Modified A20FMDV2 peptides show improved stability and activity. These analogues target tumor-associated αvβ6 integrins, enhancing their potential for drug delivery applications.
Area of Science:
- Biochemistry
- Peptide Chemistry
- Drug Delivery
Background:
- The peptide A20FMDV2 targets the tumor-associated αvβ6 integrin.
- A20FMDV2 has potential as a drug delivery vector but suffers from poor plasma half-life due to protease susceptibility.
Purpose of the Study:
- To synthesize and evaluate A20FMDV2 analogues with enhanced plasma stability and maintained αvβ6 integrin binding affinity.
- To improve the therapeutic potential of A20FMDV2 by increasing its half-life and reducing degradation.
Main Methods:
- Synthesis of fourteen A20FMDV2 analogues with non-proteinogenic amino acid substitutions (Lys16, Leu13).
- Synthesis of six A20FMDV2 analogues with modified N- and C-termini.
- Functionalization of promising analogues with diethylenetriaminepentaacetic acid (DTPA) for radiolabeling with indium-111.
- In vitro activity assays and plasma stability studies.
Main Results:
- Analogues with modified terminal motifs retained strong binding to the αvβ6 integrin.
- A20FMDV2 variants with N-terminal d-Asn and C-terminal d-Thr demonstrated improved in vitro activity.
- These specific variants exhibited reduced susceptibility to plasma degradation, indicating enhanced stability.
Conclusions:
- Modification of the N- and C-termini of A20FMDV2 can significantly improve its plasma stability.
- The developed analogues maintain high affinity for the αvβ6 integrin, preserving their potential as targeted drug delivery vectors.
- These findings pave the way for more effective peptide-based therapeutics targeting αvβ6 integrin-expressing tumors.
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