Successful PhD Defence on High Through-put Screening of Schistosoma

Successful PhD student with bottle of wine in labOn January 16, 2018, IBERS-funded PhD student Kezia Whatley successfully defended her thesis entitled: “Synergistic application of high-throughput screening (HTS) and high content imaging (HCI) technologies with in silico drug repositioning techniques to identify new chemotherapeutic targets in Schistosoma mansoni”. Supervised by Prof. Karl Hoffmann, Kezia helped set up a HTS platform based on a sister screening platform at the London School of Hygiene and Tropical Medicine as part of her PhD. This HTS platform, named Roboworm, enables the screening of compound collections against the larval stage of S. mansoni. This parasite is one of several Schistosoma sp., responsible to for causing the neglected tropical disease schistosomiasis which affects >218 million people globally. Additionally to this, Kezia also set up a simple and cost efficient cytotoxicity assay against Human Caucasian Hepatocyte Carcinoma (HepG2) cells, to enable an initial determination of compound toxicity. The skill sets obtained during her PhD have enabled Kezia to continue working in Prof. Karl Hoffmann’s research group on two research projects. Initially, Kezia worked collaboratively with industrial and academic partners to screen new compound libraries against S. mansoni. This project, funded by the Life Sciences National Research Network Wales, facilitated the screening and publication of several compounds synthesised by PhD students in IBERS and collaborations between IBERS and other academic institutions. Kezia is currently working on a Welsh Government funded Life Sciences Bridging Fund project to develop Roboworm for screening other parasitic worm species such as Fasciola hepatica and Haemonchus contortus. Both of these parasites are responsible for causing high economic loss in the farming industry (~£110 million per annum in the UK alone). These translational projects and collaborations have identified that there is a demand for a screening service against both veterinary and biomedically relevant parasites. It is hoped that continued development of the Roboworm platform will enable medicinal chemists to screen previously untested compounds against these parasites, which will help identify new antiparasitic compounds urgently needed for combating human and animal pathogens.

By Ifat Parveen

Potential class of HIV-1 integrase inhibitors

Cameron Garty is currently completing an MPhil in natural product drug discovery and medicinal chemistry in Dr Shah’s research group.

To date, seventy-eight million people in the world, have become infected with HIV and over thirty-five million deaths have resulted from HIV/AIDs and related diseases. Currently, there are between thirty-six million people living with HIV, of which two million are under the age of fifteen. The number of people with HIV receiving treatment in resource-poor countries has dramatically increased over the past decade. However, variations of HIV that develop with current medicines have led to drug-resistant strains; the search for successful therapies has not been more imperative. Understanding the function of the CD4 cells has made it possible for scientists to design antiretroviral drugs that inhibit the production of HIV by halting the process at the different stages of the life cycle. These include entry inhibitors, fusion inhibitors, reverse transcriptase inhibitors; nucleotide inhibitors, non-nucleotide inhibitors, integrase inhibitors and protease inhibitors. Currently, treatment does not cure HIV. The antiretroviral drug (ARV) therapy struggles with the issues of patient obedience, side effects, the huge cost and evolving drug resistances. More drugs against HIV targets are critical in preventing the HIV epidemic and the long term efficacy of ART. Lithospermic acid, isolated from red sage (Salvia miltiorrhiza), has been shown to inhibit HIV-1 integrase with a reported IC50 value of 0.48 M (Abd-Elazem et al., 2002). Further studies have shown it to strongly suppress HIV-1 infection in model organisms (H9 cells) with a reported IC50 value of 2 μM (Abd-Elazem et al., 2002). Currently, lithospermic acid is undergoing clinical trials as an anti-HIV drug. The overall aim of the project is to identify novel clinically active anti-HIV drugs. The objectives of the study are to synthesise a portfolio of compounds structurally similar to lithospermic acid and test against HIV-1 integrase.