Chemoenzymatic\nSynthesis of DNP-Functionalized FGFR1-Binding\nPeptides as Novel Peptidomimetic Immunotherapeutics for Treating Lung\nCancer

Receptor-binding peptides are promising candidates for\ntumor target\ntherapy. However, the inability to occupy “hot spots”\non the PPI interface and rapid metabolic instability are significant\nlimitations to their clinical application. We investigated a new strategy\nin which an FGFR1-binding peptide (Pep1) was site-specifically functionalized\nwith the dinitrophenyl (DNP) hapten at the C-terminus. The resulting\nPep1-DNP conjugates retained FGFR1 binding affinity and exhibited\na similar potency in inhibiting FGF2-dependent cell proliferation,\ncomparable to that of native Pep1 in vitro. In addition, three conjugates\ncould recruit anti-DNP antibodies onto the surface of cancer cells,\nthereby mediating the CDC efficacy. In vivo pharmacokinetic studies\nand antitumor studies demonstrated that optimal conjugate <b>9</b> exhibited significantly prolonged half-lives and improved antitumor\nefficacy without prominent toxicity compared to those of native Pep1.\nThis is a general and cost-effective approach for generating peptidomimetic\nimmunotherapeutics with multiple antitumor mechanisms that may have\nbroad applications in cancer therapy.