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Structure based design of angiotensin-converting enzyme (from Anopheles gambiae) inhibitors as mosquitocides


Department of Biology & Biochemistry

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Prof Ravi Acharya Applications accepted all year round Self-Funded PhD Students Only

About the Project

The mosquitoes of the Anopheles and Aedes genus are some of the most deadly insects to humans because of their effectiveness as vectors of malaria and a range of arboviruses, including yellow fever, dengue, chikungunya, West Nile and zika. Nearly half the World’s population is at risk from malaria transmitted by adult female Anopheles and a similar number live in areas at risk from arboviruses that are vectored by Aedes spp. The close association of Aedes spp. with urbanisation in tropical and sub-tropical countries presents particular challenges in disrupting the cycle of arbovirus infections.

The lack of effective vaccines for malaria and the appearance of resistance to antimalarials together with the absence of treatments for dengue, chikungunya, West Nile and zika has focused attention on integrated vector control management of both Anopheles and Aedes spp based on environmental/cultural management, biological and chemical control. The use of insecticides from different chemical classes is a key component of the integrated strategy against both An. gambiae and Ae. aegypti, but the increasing problem of insecticide resistance means that new compounds with different modes of action are urgently needed to replace chemicals that fail to control resistant mosquito populations.

We have shown that feeding inhibitors of peptidyl dipeptidase A to mosquito larvae leads to stunted growth and mortality. These compounds, however, were designed to inhibit mammalian form of the angiotensin converting enzyme (ACE) and hence often lack potency and selectivity as inhibitors of the insect peptidase (1, 2).

The objective this PhD project is to stimulate and execute innovative research ideas leading to the discovery of new chemical entities with novel mechanisms of action that can be developed for the safe and effective control of mosquito vectors.

The project will be based in the Acharya group in the Department of Biology and Biochemistry at Bath. The student will be performing structural (X-ray crystallography using the Diamond Synchrotron Source) and mechanism-of-action studies to discover mosquitocide leads that inhibit new or existing targets in ways that lessen the chance of resistance.

Applicant profile:

Applicants should hold, or expect to receive, a First Class or high Upper Second Class UK Honours degree (or the equivalent qualification gained outside the UK) in Biochemistry/Molecular Biology/Structural Biology. A master’s level qualification would also be advantageous. Non-UK applicants must meet our English language entry requirement http://www.bath.ac.uk/study/pg/apply/english-language/index.html.

How to apply:

Informal enquiries are welcomed and should be addressed to Prof Ravi Acharya, [Email Address Removed].

Formal applications should be made via the University of Bath’s online application form for a PhD in Biochemistry:
https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUBB-FP01&code2=0014

Please ensure that you quote the supervisor’s name and project title in the ‘Your research interests’ section.

More information about applying for a PhD at Bath may be found here:
http://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/

Anticipated start date: 28 September 2020. Other start dates are possible, by arrangement.

Funding Notes

This project is open to UK/EU/Overseas applicants who can source their own external sponsorship or who can finance their own studies (tuition fees, bench fees and living costs).

Details of tuition fees may be found here:
https://www.bath.ac.uk/corporate-information/faculty-of-science-postgraduate-research-tuition-fees-2020-21/

Bench fees would be agreed with the lead supervisor.

A typical postgraduate budget for living costs may be found here:
https://www.bath.ac.uk/publications/postgraduate-budget/attachments/postgraduate-overall-budget-2019-20.pdf

References

1: Cashman JS, Cozier GE, Harrison C, Isaac RE, Acharya KR. Crystal structures of angiotensin-converting enzyme from Anopheles gambiae in its native form and with a bound inhibitor. Biochem J. 2019, 476: 3505-3520.

2: Abu Hasan Z', Williams H, Ismail NM, Othman H, Cozier GE, Acharya KR, Isaac RE. The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae. Sci Rep. 2017, 7: 45409.


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