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A SOCS3 Competitor Protein Overcomes Leptin Resistance By
Activating The JAK/STAT3 Signaling In Hypothalamic Neurons

Yerim Kang, Sukyeong Jeong, Sujung Lee, Dabin Guk, Moonyoung Choi, Eunna Chung and Daewoong Jo
Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea

BACKGROUND AIM
The main obstacle to treat patients with obesity is inappropriate appetite The aim of this study is to develop a cell-permeable recombinant protein
regulation induced by leptin resistance. Suppressor of cytokine signaling 3 which competes with SOCS3 and recovers the leptin signaling in obese
(SOCS3) binds to leptin receptor (ObRb) and blocks the leptin signaling, patients. The recombinant protein should be homogenous, soluble and
and it implies that development of a SOCS3 competitor would be a way to thermostable at 37℃, and overcomes leptin resistance in hypothalamic
treat obesity by overcoming leptin resistance. neurons.
METHODS
To develop a SOCS3 competitor, the SH2 domain of human SOCS3 was truncated, and to the truncate the advanced macromolecule
transduction domain (aMTD) and solubilization domain B (SDB) were conjugated to improve cell permeability and solubility, respectively. The
recombinant protein, designated as cell-permeable (CP)-truncated SOCS3 SH2 domain (SD), was purified from E. coli and characterized about
homogeneity, solubility, thermal stability and anti-obesity efficacy in diet-induced obesity (DIO) mouse model.

RESULTS

Figure 1. CP- △SOCS3 Has Anti-Obesity Figure 4. P2-1-32B, Which Has p-Tyr Binding Sites, Receptor
Efficacy But Is Heterogeneous Binding Sites And SDB, Is Highly Soluble And Homogenous
A B A B

C
Reducing &
Non-Reducing Gels HPLC
Reducing Non-Reducing
M M
Figure 5. M830-P2-1-32B Is Stable With Thermal Stress And
Overcomes Leptin Resistance In Hypothalamic Neurons
A B
Figure 2. Design Of New Anti-Obesity Drug Candidates With
Leptin Receptor Interactive Sites In The SH2 Domain Of SOCS3

A B
Figure 6. CP-SD (M363-P2-1-32B) Is Soluble, Homogeneous And
Thermostable, Binds To Leptin Receptor, And Has Anti-Obesity Efficacy
A E

Figure 3. M524-P2-1-6 With p-Tyr Binding Sites, R71 And R94,
Binds To Leptin Receptor And Overcomes Leptin Resistance
B
A B

C
C D

CONCLUSION REFERENCES CONTACT INFORMATION
CP-SD is homogenous, highly soluble and Chung et al. (2020) Science Advances, 6: eaba 1193 Sukyeong Jeong, Ph.D
thermostable at 37℃ and has anti-obesity Lim et al. (2013) Clinical Cancer Research, 19: 680-690
efficacy by overcoming leptin resistance. These Cellivery Therapeutics, Inc.
results suggest that CP-SD is a promising Lim et al. (2013) Biomaterials, 34: 6261-6271 jeongsy@cellivery.com
therapeutic protein to treat severe obesity by Lim et al. (2012) Molecular Therapy, 20: 1540-1549
restoring leptin sensitivity and suppressing Jo et al. (2005) Nature Medicine, 11: 892-898 +82-2-3151-8900
abnormally elevated appetite.
Jo et al. (2001) Nature Biotechnology, 19: 929-933 S4-3 신진과학자