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Investigation of salivary peptides as SARS-CoV-2 entry inhibitors


   Dental School

  ,  Thursday, June 30, 2022  Self-Funded PhD Students Only

About the Project

The global pandemic caused by the emergence of a novel Coronavirus in Wuhan during 2019 has had a huge impact on all aspects of human health. Among the many features that make the virus SARS-CoV-2 difficult to control are the periods of viral shedding that either precede symptoms or occur in individuals that remain asymptomatic. Therefore the oral cavity is not only an important site of viral entry but also acts as s significant source of infective material. Consequently key steps in addressing COVID-19 include understanding the sensitivity of different oral tissues to infection, assessing the importance of salivary components in priming the virus for entry, and determining if the anti-viral properties previously assigned to molecules naturally present in the mouth impact on adhesion and cell entry. It is the aim of this PhD project to develop a method to monitor the binding of viral Spike protein to oral cell lines and use this to screen for fusion inhibitors that could be utilised in therapeutic interventions that include the adaptation of oral mouthwashes to include components that can limit viral entry and onward transmission of primed virions. 

We currently have access to recombinant SARS-CoV-2 Spike protein, three oral cells lines and reagents that have allowed us to establish the expression of theproteins including ACE2, Furin and TMPRSS2. In addition, we know that under experimental conditions that upon exposure to Spike these cell lines form Syncytia, multi-nucleate cells formed by membrane fusion. Preliminary work shows that there formation can be delayed by the addition of a inhibitory peptide already described in the literature. The PhD will involve training in molecular and biochemical techniques that will enable the student to refine the experimental conditions for profiling cellular responses. The second year will exploit the techniques and conditions established to screen a number of naturally occurring anti-viral peptides found in saliva and is intended to produce insights into how important these molecules could be in protecting people from infection and also limiting the ability of an individual’s saliva to transmit infective material. It is projected that in the final year of study the most promising material and platforms will form the basis for establishing collaborations within Dundee, SLS Drug Discovery Unit, and internationally, i.e. NMI, Tuebingen, Germany.

Studies will be performed in the Molecular Biology Facility of Dundee Dental School, and students will obtain a range of skills associated with cell biology, protein analysis, transcriptional profiling and bioinformatics. The project requires a detailed understanding of Oral Science, and collaboration with DDS clinical colleagues who have expertise in Saliva, Taste bud biology, and Biomarkers will provide the applicant with a unique skill set. The supervisors have previously been successful in obtaining seed funding for this research area and are registered with the MRC/Wellcome protein portal that enables access to key COVID-19 reagents. Initial studies have been promising and the project has a high likelihood of generating significant insights into our understanding the role of the oral cavity in COVID-19 infections. 

For informal enquiries about the project, contact Dr David Edwards ()

For general enquiries about the University of Dundee, contact

QUALIFICATIONS

Applicants must have obtained, or expect to obtain, a UK honours degree at 2.1 or above (or equivalent for non-UK qualifications), and/or a Masters degree in a relevant discipline. For international qualifications, please see equivalent entry requirements here: www.dundee.ac.uk/study/international/country/.

English language requirement: IELTS (Academic) overall score must be at least 6.5 (with not less than 6.0 in writing and not less than 5.5 in reading, listening and speaking). The University of Dundee accepts a variety of equivalent qualifications; please see full details of the University’s English language requirements here: www.dundee.ac.uk/guides/english-language-requirements.

APPLICATION PROCESS

Step 1: Email Dr David Edwards () to (1) send a copy of your CV and (2) discuss your potential application and any practicalities (e.g. suitable start date).

Step 2: After discussion with Dr Edwards, formal applications can be made via our direct application system. When applying, please follow the instructions below:

Candidates must apply for the Doctor of Philosophy (PhD) degree in Dentistry (non-clinical) using our direct application system: apply for Dentistry.

Please select the study mode (full-time/part-time) and start date agreed with the lead supervisor.

In the Research Proposal section, please:

-       Enter the lead supervisor’s name in the ‘proposed supervisor’ box

-       Enter the project title listed at the top of this page in the ‘proposed project title’ box

In the ‘personal statement’ section, please outline your suitability for the project selected.


Funding Notes

Currently there is no funding attached to this project, and the successful applicant would need to provide the funding for tuition fees and living expenses via external sponsorship or self-funding. However, the supervisory team is applying for schemes that would offer either complete or partial funding.

References

Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8.
Mei Zhong B-pL, Hong-bin Gao, Andrew J Young, Xin-hong Wang, Chang Liu, Kai-bin Wu, Ming-xiao Liu, Jian-ming Chen, Jiang-yong Huang, Learn-han Lee, Cui-ling Qi, Lin-hu Ge, Li-jing Wang. Significant expression of FURIN and ACE2 on oral epithelial cells may facilitate the efficiency of SARS-CoV-2 entry. 2020.
To KK, Tsang OT, Chik-Yan Yip C, Chan KH, Wu TC, Chan JMC, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis. 2020.
Xu R, Cui B, Duan X, Zhang P, Zhou X, Yuan Q. Saliva: potential diagnostic value and transmission of 2019-nCoV. Int J Oral Sci. 2020;12(1):11.
Treindl F, Ruprecht B, Beiter Y, Schultz S, Dottinger A, Staebler A, et al. A bead-based western for high-throughput cellular signal transduction analyses. Nat Commun. 2016;7:12852.
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020.
Malamud D, Abrams WR, Barber CA, Weissman D, Rehtanz M, Golub E. Antiviral activities in human saliva. Adv Dent Res. 2011;23(1):34-7.
Castagnola M, Cabras T, Vitali A, Sanna MT, Messana I. Biotechnological implications of the salivary proteome. Trends Biotechnol. 2011;29(8):409-18.

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