Chemoenzymatic Synthesis of DNP-Functionalized FGFR1-Binding Peptides as Novel Peptidomimetic Immunotherapeutics for
Xiaohui Li1, Haiyan Liu2, Shengjie Ding1
1State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Abstract:
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.
Insights
This study developed a modified peptide (Pep1-DNP) for cancer therapy, enhancing its stability and enabling dual action against tumors. The new conjugate showed improved efficacy and safety in preclinical models.
Area of Science:
- Biochemistry
- Immunology
- Oncology
Background:
- Receptor-binding peptides show promise for tumor targeting but face limitations like poor target site occupancy and metabolic instability.
- Developing stable and effective peptide-based therapeutics is crucial for advancing cancer treatment.
Purpose of the Study:
- To engineer a fibroblast growth factor receptor 1 (FGFR1)-binding peptide (Pep1) with enhanced stability and multiple antitumor mechanisms.
- To evaluate the efficacy and safety of Pep1 functionalized with a dinitrophenyl (DNP) hapten (Pep1-DNP) as a novel cancer immunotherapeutic.
Main Methods:
- Site-specific C-terminal functionalization of Pep1 with the DNP hapten to create Pep1-DNP conjugates.
- In vitro assays to assess FGFR1 binding affinity, inhibition of FGF2-dependent cell proliferation, and antibody-dependent cell-mediated cytotoxicity (CDC).
- In vivo pharmacokinetic studies and antitumor efficacy assessments in preclinical cancer models.
Main Results:
- Pep1-DNP conjugates maintained FGFR1 binding affinity and inhibited cell proliferation similarly to native Pep1 in vitro.
- Conjugates successfully recruited anti-DNP antibodies to cancer cells, mediating CDC.
- Optimal conjugate 9 demonstrated significantly prolonged half-lives, improved antitumor efficacy, and reduced toxicity compared to native Pep1 in vivo.
Conclusions:
- Site-specific functionalization with DNP is a viable strategy to create stable peptidomimetic immunotherapeutics.
- Pep1-DNP conjugates offer a dual-mechanism approach (direct inhibition and antibody-mediated immunity) for cancer therapy.
- This generalizable and cost-effective method holds broad potential for developing novel cancer therapeutics.
