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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2015.1
- 수록면
- 1,251 - 1,257 (7page)
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Purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulationof the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR.
Materials and Methods: We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silicoscreening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo.
Results: A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependentmanner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice.
Conclusion: Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.
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참고문헌 (23)
참고문헌 신청
Abifadel M / 2003 / Mutations in PCSK9 cause autosomal dominant hypercholesterolemia / Nat Genet 34 : 154 ~ 156
Andricopulo AD / 2009 / Structure-based drug design strategies in medicinal chemistry / Curr Top Med Chem 9 : 771 ~ 790
Bottomley MJ / 2009 / Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants / J Biol Chem 284
Canto JG / 2003 / Major risk factors for cardiovascular disease:debunking the “only 50%” myth / JAMA 290 : 947 ~ 949
Cohen JC / 2006 / Sequence variations in PCSK9, low LDL, and protection against coronary heart disease / N Engl J Med 354 : 1264 ~ 1272
Andricopulo AD / 2009 / Structure-based drug design strategies in medicinal chemistry / Curr Top Med Chem 9 : 771 ~ 790
Bottomley MJ / 2009 / Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants / J Biol Chem 284
Canto JG / 2003 / Major risk factors for cardiovascular disease:debunking the “only 50%” myth / JAMA 290 : 947 ~ 949
Cohen JC / 2006 / Sequence variations in PCSK9, low LDL, and protection against coronary heart disease / N Engl J Med 354 : 1264 ~ 1272
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