Citation: Junli Wang, Cen Liu, Hongliu Yang, Tao Ma, Yonggang Liu, Fener Chen. Intramolecularly lactam stapled oxyntomodulin analogues inhibit cancer cell proliferation in vitro[J]. Chinese Chemical Letters, ;2023, 34(4): 107920. doi: 10.1016/j.cclet.2022.107920 shu

Intramolecularly lactam stapled oxyntomodulin analogues inhibit cancer cell proliferation in vitro

Junli Wang ^{a, b} ,
Cen Liu ^c ,
Hongliu Yang ^c ,
Tao Ma ^c ,
Yonggang Liu ^c ,
Fener Chen ^{a, *,}

a.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
b.
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
c.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Beijing 102488, China

rfchen@fudan.edu.cn

Received Date: 5 September 2022
Revised Date: 8 October 2022
Accepted Date: 18 October 2022
Available Online: 20 October 2022

Figures(1)

As a glucagon (GCG) receptor (GCGR) and glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) dual agonist, oxyntomodulin (OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions [Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of HeLa cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types. Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC₅₀ value of 115.1 µmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.
- Oxyntomodulin analogues,
- Intramolecular lactam,
- Dual GCGR/GLP-1R activations,
- Anti-PANC-1 proliferation
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沈阳化工大学材料科学与工程学院沈阳 110142