LICAMM Repurposing BACE1 inhibitors for cardiovascular disease

Summary

Cardiovascular disease is the biggest killer for individuals with type 2 diabetes. Endothelial cells play a key role in regulating the responses of blood vessels to a number of stimuli, such as hormones and blood flow. Compromised responses, as seen in individuals with type 2 diabetes, results in impaired blood flow leading to stroke or heart attack. Therefore, despite all the efforts thus far, another treatment strategy is urgently needed.

Elevated activity levels of the ß-secretase (BACE1) have an historic link to the development of Alzheimer’s disease, via increased beta-amyloid (Aβ) production. However, we have also shown that increased BACE1 activity also drives the progression of vascular complications associated with type 2 diabetes.

Aim

The aim of this PhD project is to generate, novel and clinically relevant compounds to inhibit BACE1 for the long term goal of improving patient cardiovascular health. We will achieve this by combining expertise in small molecule design within the medicinal chemistry and chemical biology group (MCCB), with expertise in cardiovascular and metabolic physiology within the Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM).

Project

We will identify and synthesise potent BACE1 inhibitors by drawing on a wealth of BACE1 drug discovery literature for Alzheimer’s disease to accelerate the design process. The student will then test a selection of compounds to examine their effect on improving vascular function using real time functional assays and state of the art imaging techniques in order to identify which the best candidates which could go on and form therapies for patients with cardiovascular disease. The outcomes from this project could have huge potential for improving cardiovascular health through ‘drug-repurposing’.

Training

You will have advantage in working in a multidisciplinary environment, gaining experience in physiology and medicinal chemistry. The student will receive training in a range of in vitro and in vivo techniques including isolation and culture of primary cells (human and rodent), immunohistochemistry, Western Blotting, vascular contractility experiments (organ bath and wire myography) and in vivo laser speckle imaging and iontophoresis to measure vascular function in real time. The student will also receive training in chemical synthesis and medicinal chemistry strategies to optimise molecular properties and inhibitor binding, with a complementary focus on in silico fragment-based molecular design.

References

The beta secretase BACE1 regulates the expression of insulin receptor in the liver
Meakin PJ, et al., Nat. Comm., 2018, 9, 1306.

Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured
rodent myotubes
Hamilton DL, et al., Diabetologia., 2014, 57(8), 1684-92.

Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice.
Meakin PJ, et al., Sci Rep. 2018, 8, 55.

Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
Fishwick CWG, et al., J. Med. Chem. 2013, 56, 1843−1852.

Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s
disease-related pathogenesis
Cui J, et al., Cell Disc., 2015, 1, 15021.

Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal
Model
Truong AP, et al., Bioorg. Med. Chem. Lett., 2010, 20, 6231-6236.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.