The development of new antiviral agents targeting HIV-1


   Faculty of Medical Sciences Graduate School

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  Dr M Ashton  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Even before the current global COVID-19 pandemic, the threat posed to human health by viruses was extensive and although significant progress in targeting some viruses (e.g., HIV-1 and hepatitis C) has been made, challenges remain.

The development of effective small molecule drugs that target different stages of the HIV-1 replicative cycle has led to an enormous improvement in both the quality of life and life expectancy of HIV-positive individuals; the life expectancy for HIV-positive individuals that are on stable antiretroviral treatment is similar to the general population. However, many of these agents have poor safety profiles, require daily dosing, and have cross-resistance with other agents in the same class. Therefore, in order to meet the UN goal of eradicating the current HIV/AIDS epidemic by 2030 [1], many of those challenges will need to be overcome.

The proposed project would look to develop a new class of reverse transcriptase (RT) inhibitors (allosteric RT inhibitors) with an improved safety and pharmacokinetic profile.

RT is a key viral enzyme that is known to interact with a number of cellular factors [2, 3] which have yet to be fully exploited as new targets for drug discovery. Previous studies by Botta et-al explored targeting RT dimerization[4, 5], and the work by Warren et-al [6, 7] suggested that a protein-protein interaction (PPI) involving RT and the cellular eukaryotic translation elongation factor 1A (eEF1A) could be targeted. eEF1A is an abundant cellular protein that is involved in the delivery of aminoacylated tRNAs to the elongating ribosome and is known to be implicated in the successful replication of a number of different RNA viruses [8].

A recent follow-up study by Rawle et-al has identified a specific region of RT that is responsible for the interaction with eEF1A [9]. This newly discovered region of RT that is required for interacting with eEF1A presents a valuable target for drug design, and indeed, the development of drugs targeting PPI interactions has emerged as a new therapeutic strategy for a range of disease states, particularly in the field of anti-infective chemotherapy.

This project will involve a collaboration between Newcastle University (Dr Mark Ashton and Dr Alessio Iannetti) and Dr Yu Gong (Chengdu YontinoTech Co. Ltd) and will look to develop novel allosteric RT inhibitors.

The multidisciplinary nature of this project represents a great opportunity for the student and would be particularly suited to a Biomedical Science, Chemistry or Pharmacy graduate and allow them to obtain valuable training in all aspects of medicinal chemistry.

The candidate should have (or expect to receive) a degree at 2:1 or above.

Chemistry (6) Medicine (26)

Funding Notes

The successful applicant will be expected to provide the funding for Tuition Fees, living expenses and maintenance. Details of the cost of the study can be found on our website. THERE IS NO ADDITIONAL FUNDING ATTACHED TO THIS PROJECT. Applicants should also be aware that additional research costs of £9,000 per annum are required (above Tuition Fees and Living Expenses) for project consumables.

References

[1] Nations U. Global Issues 2018 [10/6/2018]. Available from: www.un.org/en/sections/issues-depth/aids/.
[2] Warren K, Warrilow D, Meredith L, Harrich D. Reverse transcriptase and cellular factors: regulators of reverse transcription. Viruses 2009;1:873-94.
[3] Warrilow D, Warren K, Harrich D. Strand transfer and elongation of HIV-1 reverse transcription is facilitated by cell factors in vitro. PLoS One 2010;5(10).
[4] Grohmann D, Corradi V, Elbasyouny M, Baude A, Horenkamp F, Laufer S, et al. Small Molecule Inhibitors Targeting HIV-1 Reverse Transcriptase Dimerization. ChemBioChem 2008;9(18):916-22.
[5] Tintori C, Corona A, Esposito F, Brai A, Grandi N, Ceresola E, et al. Inhibition of HIV-1 Reverse transcriptase Dimerization by Small Molecules. ChemBioChem 2016;17:683-8.
[6] Warren K, Wei T, Li D, Qin F, Warrilow D, Lin M, et al. Eukaryotic elongation factor 1 complex subunits are critical HIV-1 reverse transcription cofactors. Proc Natl Acad Sci USA 2012;109:9587-92.
[7] Li D, Wei T, Rawle D, Qin F, Wang R, Soares D, et al. Specific interaction between eEF1A and HIV RT is critical for HIV-1 reverse transcription and a potential anti-HIV target. PLoS Pathog 2015;11:e1005289.
[8] Li D, Wei T, Abbott C, Harrich D. The unexpected roles of eukaryotic translation elongation factors in RNA virus replication pathogenesis. Microbiol Mol Biol Rev 2013;77(2):253-66.
[9] Rawle D, Dongsheng L, Swedberg J, Wang L, Soares D, Harrich D. HIV-1 Uncoating and Reverse Transcription Require eEF1A Binding to Surface-Exposed Acidic Residues of the Reverse Transcriptase Thumb Domain. mBio 2018;9:e00316-18.
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