Chemoenzymatic Synthesis of DNP-Functionalized FGFR1-Binding Peptides as Novel Peptidomimetic Immunotherapeutics for Treating Lung Cancer

Receptor-binding peptides are promising candidates for
tumor target
therapy. However, the inability to occupy “hot spots”
on the PPI interface and rapid metabolic instability are significant
limitations to their clinical application. We investigated a new strategy
in which an FGFR1-binding peptide (Pep1) was site-specifically functionalized
with the dinitrophenyl (DNP) hapten at the C-terminus. The resulting
Pep1-DNP conjugates retained FGFR1 binding affinity and exhibited
a similar potency in inhibiting FGF2-dependent cell proliferation,
comparable to that of native Pep1 in vitro. In addition, three conjugates
could recruit anti-DNP antibodies onto the surface of cancer cells,
thereby mediating the CDC efficacy. In vivo pharmacokinetic studies
and antitumor studies demonstrated that optimal conjugate 9 exhibited significantly prolonged half-lives and improved antitumor
efficacy without prominent toxicity compared to those of native Pep1.
This is a general and cost-effective approach for generating peptidomimetic
immunotherapeutics with multiple antitumor mechanisms that may have
broad applications in cancer therapy.