Calmodulin signalling as a potential therapeutic target for COVID-19 infection

Description

Project background and aims

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged in December 2019 in China as the newest member of a family of coronaviruses (CoV) and has rapidly spread worldwide.  In approximately 20% of cases, SARS-CoV-2 can invade the respiratory system of humans and cause mild to severe respiratory disorders which have been named coronavirus disease 19 (COVID-19). COVID-19 has been causing a major disruption of economic and social life of individuals due to its high transmission rate which has resulted in ~219 million cases and ~4.5 million deaths worldwide.

For virus entry, SARS-CoV-2 can utilise the angiotensin-converting-enzyme-2 (ACE2) receptors, which are highly expressed in the lungs, cardiovascular tissues, kidneys, and the gastrointestinal system. The virus binds to membrane-bound ACE2 to enter the host cells via the spike glycoprotein on SARS-CoV-2 surface. Interestingly, it has been shown that the ectodomain of ACE2 can be shed endogenously by the disintegrin metalloproteinase 17 (ADAM-17) generating a soluble form of ACE2 (sACE2) and therefore interfering with virus internalisation. In addition, oestrogen receptors regulators (eg. tamoxifen, toremifene) can affect ACE2 expression and inhibit SARS-CoV viruses.

Calmodulin (CaM), a ubiquitous calcium-binding protein, has been shown to interact with ACE2 to inhibits shedding and can modulate oestrogen receptor activity. Therefore it is hypothesised that CaM modulators constitute an attractive target for pharmacological intervention to interfere with virus entry and reduce the incidence and severity of COVID-19.

In this project, we will use a multidisciplinary approach combining protein biochemistry, biophysics, structural biology and medicinal chemistry to evaluate the therapeutic potential of calmodulin signalling in COVID-19.

Student Experience

This is an exceptional opportunity for the successful applicant to receive comprehensive research training in techniques ranging from molecular cloning, protein biochemistry, structural biology, cell biology and medicinal chemistry.

The student will be supervised by Dr Nordine Helassa (Senior Lecturer in Biochemistry) and Dr Caroline Dart (Professor in Physiology) who will provide training and support in all relevant techniques. The project will be hosted in the Department of Biochemistry, Cell and Systems Biology in the Institute of Systems, Molecular and Integrative Biology.

https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/

Applicant information

We are looking for a highly motivated student who is willing to pursue cutting-edge research within a vibrant and collegiate team. The successful applicant should have an interest in basic biomedical research and hold a minimum undergraduate qualification 2:1, or equivalent, in a life science or health-related subject.

Research project related enquiries should be made in the first instance to Dr Nordine Helassa (nhelassa@liverpool.ac.uk).

To apply please send your CV to Dr Nordine Helassa (nhelassa@liverpool.ac.uk).

Availability

Open to students worldwide

Funding information

Self-funded project

We are looking for a self-funded student who has secured funding from an independent body. There is no financial support available from Liverpool for this study.

The successful applicant will be expected to have funding in place for the tuition fees (https://www.liverpool.ac.uk/study/postgraduate-research/fees-and-funding/fees-and-costs/), consumables/bench fee (£15,000 per annum) and living expenses during their stay in Liverpool.

 

Supervisors

References

  1. Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005 Aug 26;280(34):30113-9. doi: 10.1074/jbc.M505111200.
  2. Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, Johnson RF, Olinger GG Jr, Jahrling PB, Laidlaw M, Johansen LM, Lear-Rooney CM, Glass PJ, Hensley LE, Frieman MB. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93. doi: 10.1128/AAC.03036-14.
  3. Lambert DW, Clarke NE, Hooper NM, Turner AJ. Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. FEBS Lett. 2008 Jan 23;582(2):385-90. doi: 10.1016/j.febslet.2007.11.085.
  4. García Pedrero JM, Del Rio B, Martínez-Campa C, Muramatsu M, Lazo PS, Ramos S. Calmodulin is a selective modulator of estrogen receptors. Mol Endocrinol. 2002 May;16(5):947-60. doi: 10.1210/mend.16.5.0830.