Design and Discovery of New Collagen V-Derived FGF2-Blocking Natural Peptides Inhibiting Lung Squamous Cell Carcinoma In Vitro and In Vivo

  • J Med Chem. 2024 Aug 8;67(15):12660-12675. doi: 10.1021/acs.jmedchem.4c00654.
Keli Kuang  1 ,  Xiang Chen  1 ,  Maolin Wang  1 ,  Weijing Han  2 ,  Xue Qiu  3  4 ,  Taoli Jin  2 ,  Rong Xu  2 ,  Bing Yuan  2 ,  Meiqi Qian  3  4 ,  Chunyan Li  1 ,  Run Xiang  5 ,  Fei Li  1 ,  Shuwen Zhang  1 ,  Zi Yang  1 ,  Junrong Du  1 ,  Dapeng Li  1 ,  Chun Zhang  1 ,  Qiantao Wang  1 ,  Tao Jia  1
Affiliations
  • 1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 2. Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.
  • 3. Key Laboratory of Marine Drug, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 4. Laboratory forMarine Drugs and Bioproducts, Qingdao National Laboratory for Marine Scienceand Technology, Ocean University of China, Qingdao 266237, China.
  • 5. Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China.
PMID: 39045829 DOI: 10.1021/acs.jmedchem.4c00654
Abstract

Aberrant FGF2/FGFR signaling is implicated in lung squamous cell carcinoma (LSCC), posing treatment challenges due to the lack of targeted therapeutic options. Designing drugs that block FGF2 signaling presents a promising strategy different from traditional kinase inhibitors. We previously reported a ColVα1-derived fragment, HEPV (127AA), that inhibits FGF2-induced angiogenesis. However, its large size may limit therapeutic application. This study combines rational peptide design, molecular dynamics simulations, knowledge-based prediction, and GUV and FRET assays to identify smaller peptides with FGF2-blocking properties. We synthesized two novel peptides, HBS-P1 (45AA) and HBS-P2 (66AA), that retained the heparin-binding site. Both peptides demonstrated anti-LSCC and antiangiogenesis properties in cell viability and microvessel network induction assays. In two LSCC subcutaneous models, HBS-P1, with its affinity for FGF2 and enhanced penetration ability, demonstrated substantial therapeutic potential without apparent toxicities. Our study provides the first evidence supporting the development of Collagen V-derived natural peptides as FGF2-blocking agents for LSCC treatment.

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