Modified ADAM10 Prodomain Peptides Protease Resistance
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Solution Overview
Problem
Current small molecule inhibitors for ADAM10 are non-specific, leading to unwanted side effects and hindering their development as pharmaceutical drugs due to poor pharmacokinetic properties and susceptibility to cleavage by furin and meprin proteases.
Innovation Solution
Development of modified ADAM10 prodomain peptides with specific amino acid substitutions at furin and meprin recognition sites, along with pegylation, to enhance stability and reduce cleavage, thereby increasing their efficacy as ADAM10 inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule inhibitors are used to inhibit ADAM10 activity, then ADAM10 biological activities are inhibited, but the inhibitors are non-specific and cause unwanted side effects
Solution Approach 1:
The invention uses peptide segments derived from the ADAM10 prodomain (specifically amino acids 23-211) as inhibitors. These peptide segments are designed to specifically interact with and inhibit ADAM10 activity through their unique amino acid sequence and structural features, achieving specificity through the segmented peptide structure rather than small molecule inhibition
Solution Approach 2:
The peptide inhibitor contains specific local regions with particular amino acid sequences (including furin and meprin recognition sites) that are responsible for binding to and inhibiting ADAM10. The local quality of the peptide sequence at different positions provides specific interaction characteristics that enable selective inhibition without affecting other ADAM family members
2Reliability
If wild type ADAM10 prodomain peptides are used, then they can inhibit ADAM10 activity, but they are susceptible to cleavage by furin and meprin proteases resulting in poor pharmacokinetic properties
Solution Approach 1:
The peptide sequence is designed with modifications at furin and meprin recognition sites that prevent proteolytic cleavage before it can occur. Specifically, amino acid substitutions are made at positions recognized by furin (e.g., positions 26-29, 52-55) and meprin (e.g., positions 34-36, 62-63, 88-89, 136-138, 169-170, 176-178) to block their proteolytic activity against the peptide inhibitor
Solution Approach 2:
The amino acid sequence parameters of the peptide are modified through specific substitutions at critical positions. For example, changing amino acids at furin recognition sites (such as replacing RxxR motifs) and meprin sites alters the peptide's susceptibility to proteolytic cleavage, thereby improving its stability and pharmacokinetic properties while maintaining inhibitory activity
Data Source
AI summary
Provided are modified isolated ADAM10 modulating peptides and methods of using the same to modulate ADAM10 biological activities, inhibit ADAM10 biological activities associated with diseases, disorders, or conditions in subjects, including but not limited to decreasing inflammation and inhibiting undesirable cell proliferation. In some embodiments, the modified isolated ADAM10 modulating peptides are based on SEQ ID NO: 3 or SEQ ID NO: 4, and in some embodiments include modifications at or near the N-terminal and/or the C-terminal ends of the disclosed peptides as well as substitutions, insertions, and deletions at one or more amino acid positions of the ADAM10 prodomain peptides disclosed herein.