3.10 Cell-penetrating peptide sequence in IRX4 homeodomain
TFs were considered as undruggable targets. Several approaches to target
these TFs, such as inhibiting the protein-protein interactions and
TF-DNA binding have been demonstrated in recent years80. DNA has been the
target for various antiviral, anti-cancer and antimicrobial drugs
wherein ligands bind to the major groove for inhibiting DNA-protein
interactions 81.
Interactions of short peptides with DNA and their effectiveness as
anti-tumour, antibacterial or anti-inflammatory have recently been
gaining attention. These peptides despite being an attractive entity,
need work for improving their stability and their ability to penetrate
the cells 82. Cell
penetrating peptides (CPPs) have shown to be a potential therapeutic
delivery agent entering cells via endocytosis. These CPPs have been
found to be positively charged due to presence of several
Arginine/lysine residues83. To check the
efficacy of the homeodomain penetrating the cell membrane, we used
different tools and databases including CPP site2.084, a database of
cell-penetrating peptides and SkipCPP-Pred61. Using the CPP
site2.0, we found more than 50% similarities in the C-terminal
sequence, residues from 184-204 (MTLTQVSTWFANARRRLKKEN) of IRX4. The
presence of positively charged amino acids in the C-terminal region
highlights the potential of this region to be effective in cell
penetration.
Additionally, this sequence from C-terminal homeodomain was subjected to
SkipCPP-Pred to predict the effectiveness of this sequence (Table 6).
The full-length 62 amino acid homeodomain had a low prediction
confidence of 0.57 compared to the C-terminal residues, highlighting
their potential to be in the class of cell penetrating peptides. The
C-terminal sequence of IRX4 shares similarity with other IRXs. However,
N-terminal of the homeodomain in all the IRX proteins offer specificity
to these peptides.