Search a new PCSK9 inhibitor using techniques of drug planning based on a target structure

• Grant number: 20/06490-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2020
• End date: June 30, 2022
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Mario Hiroyuki Hirata
• Grantee: Vitor Galvão Lopes
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population, AP.TEM

Abstract

Familial Hypercholesterolemia (HF) is a genetic disease that causes the increase of LDL in the bloodstream, originating from mutations in genes that express proteins like: APOB, LDLr, LDLRAP1 and PCSK9. With increased LDL, an increased risk of HF patients develops cardiovascular disease. Individuals with this pathology have extremely high cholesterol levels, ranging from 200 mg/dL to 1000 mg/dL depending on the inheritance form (heterozygous or homozygous). The conventional treatment of dyslipidemias involves the use of statins that inhibit the synthesis of cholesterol, that is, they act in the production of cholesterol by the liver, but in the case of HF, these drugs do not present satisfactory results, given the specific characteristics of the disease. However, new treatments based on the inhibition of PCSK9 (convertase subtilisin/kexine type 9) are promising for the reduction of cholesterol in patients with HF. The PCSK9 gene encodes proteins that participate in the process of cholesterol endocytosis and controlling the recycling LDL receptor, accounting for about 2% of cases of HF taking into account its mutation gain-in-function. Another important mutation in the gene causes loss-of-function, in patients presenting this mutation in specific, is a type of protective mutation, decreasing LDL-c levels. However, only two drugs are approved by the FDA (Evolocumab and Alirocumabe) as a form of secondary treatment for dyslipidemias, but it is costly and costly to administer. Against this background, the search for new PCSK9 inhibitor drugs is eminent. Through the design of new drugs aided by computer, one can look for new possible inhibitors that have chemical complementarity capable of inhibiting the target. Thus, through Structure Based Virtual Screening (SBVS) strategy, it will be able to search for new molecular structures that have complementarity with PCSK9 in order to compete for the active site and thus diminish its function.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LOPES, VITOR GALVAO; DE BRITTO CHAVES FILHO, ADRIANO; YOSHINAGA, MACROS YUKIO; HIRATA, MARIO HIROYUKI; FERREIRA, GLAUCIO MONTEIRO. Carnitine palmitoyl transferase I: Conformational changes induced by long-chain fatty acyl CoA ligands. JOURNAL OF MOLECULAR GRAPHICS & MODELLING, v. 112, p. 7-pg., 2022-05-01. (20/06490-3, 21/11205-9)

LOPES, VITOR GALVAO; DE OLIVEIRA, VICTOR FERNANDES; DATI, LIVIA MENDONCA MUNHOZ; NASLAVSKY, MICHEL SATYA; FERREIRA, GLAUCIO MONTEIRO; HIRATA, MARIO HIROYUKI. Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, v. N/A, p. 9-pg., 2023-03-25. (21/11205-9, 16/12899-6, 18/11917-6, 20/06490-3)