Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells

Publication date: Available online 4 April 2019Source: Biochimica et Biophysica Acta (BBA) - Proteins and ProteomicsAuthor(s): Varun Kumar, P. Sharma, H.R. Bairagya, S. Sharma, T.P. Singh, Purnima Kaul TikuAbstractIn mammalian cells, human 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting endoplasmic reticulum (ER) bonded enzyme, plays a central role in the cholesterol homeostasis via the negative feedback mechanism. The present study indicates that the interactions of novel peptides with the catalytic domain of HMGCR, provides an alternative therapeutic candidate for reducing cholesterol. The potential natural origin of HMGCR peptide inhibitors were filtered from the peptide library using the molecular docking, which revealed three strong candidates for inhibition. This information was used for synthesizing peptides, which were evaluated for inhibition against HMGCR. The stronger docking interactions were confirmed by experimental dissociation constant (KD) values of 9.1 × 10−9 M, 1.4 × 10−8 M and 1.2 × 10−8 M for peptides NALEPDNRIESEGG (Pep-1), NALEPDNRIES (Pep-2) and PFVKSEPIPETNNE (Pep-3) respectively. The immunological based interactions show a strong evidence of peptide-HMGCR complexes. The LDL uptake showed enhancements after treatments with peptides in the extracellular environment of HepG2 cells, which was further, corroborated through increase in the immunofluorescence signal of the localized LDL-R protein expressio...
Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - Category: Biochemistry Source Type: research