TY - JOUR
T1 - From virus to diabetes therapy
T2 - Characterization of a specific insulin-degrading enzyme inhibitor for diabetes treatment
AU - Nash, Yuval
AU - Ganoth, Assaf
AU - Borenstein-Auerbach, Nofit
AU - Levy-Barazany, Hilit
AU - Goldsmith, Guy
AU - Kopelevich, Adi
AU - Pozyuchenko, Katia
AU - Sakhneny, Lina
AU - Lazdon, Ekaterina
AU - Blanga-Kanfi, Shani
AU - Alhadeff, Raphael
AU - Benromano, Tali
AU - Landsman, Limor
AU - Tsfadia, Yossi
AU - Frenkel, Dan
N1 - Publisher Copyright:
© 2021 Federation of American Societies for Experimental Biology
PY - 2021/5
Y1 - 2021/5
N2 - Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE’s catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.
AB - Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE’s catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.
UR - http://www.scopus.com/inward/record.url?scp=85104164956&partnerID=8YFLogxK
U2 - 10.1096/fj.201901945R
DO - 10.1096/fj.201901945R
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C2 - 33835493
AN - SCOPUS:85104164956
SN - 0892-6638
VL - 35
JO - FASEB Journal
JF - FASEB Journal
IS - 5
M1 - e21374
ER -
