<i>In Silico</i> Exploration and Biological Evaluation of Bispecific Peptides Derived from Anti-HER2 Antibodies and Peptide–Camptothecin Conjugates for HER2-Positive Breast Cancer

To enhance the affinity of the human epidermal growth
receptor
2 (HER2) targeted peptide developed previously, bispecific fusion
peptides P1GCGT1 and P1GCGCGT1 were designed
using an in silico approach. Molecular dynamic simulation
showed that both peptides strongly interacted with HER2 domains II
and IV. Compared with peptides targeting each single domain, P1GCGT1 and P1GCGCGT1 could bind to HER2 more
significantly and targeted HER2-positive cells specifically. Additionally,
both peptides were used to generate peptide–drug conjugates
with camptothecin (CPT), among which I-1 and I-4 were screened for enhanced cellular activity and selectivity. Biological
evaluation demonstrated that I-1 and I-4 induced cell apoptosis, promoted cell cycle arrestin S-phase, and
inhibited Topo I activity. The binding affinity assay and confocal
analysis revealed that I-1 and I-4 were
effective at targeting HER2. Moreover, I-1 and I-4 showed better stability than single targeting peptide
and presented enhanced antitumor activity and safety than CPT in tumor-bearing
mice.