Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus thatcaused the COVID-19 pandemic in 2020 and the human immunodeficiency virus (HIV) which leads to the acquired immunodeficiency syndrome (AIDS) have deeply affected the lives of more than 650 and 38 million people respectively in the last years. SARS-CoV-2 killed 6.5 million people in the last three years while HIV is accounted for more than 800 thousand deaths worldwide with a worrying yearly increase. While the COVID-19 outbreak has been tapered down by the advent of vaccines, the AIDS epidemic remains a global threat with 300 thousands new infections in 2023, as reported by the Joint United Nations Programme on HIV and AIDS reports. Despite the deployment of antiretroviral therapies, no effective
vaccine is available on the market yet for HIV. The need to promptly identify effective drugs for HIV and COVID-19 treatment requires multiple scientific efforts and technologies to quickly reduce the high cost in terms of human lives and quality of life. The biopharmaceutical research sector has extensively used the computational technologies of the last twenty years in protein sequencing, drug design, cheminformatics, and artificial intelligence to meet unmet medical needs and anticipate emergencies. In the last decade, the increase in computational power improved pharmaceutical research by drastically
reducing the time required for molecular modelling and computational chemistry calculations. With graphic processing units (GPU) becoming more accessible, computational chemistry and molecular modelling approaches are becoming more popular in drug discovery, providing atomic-level details and insights into the target-ligand molecular recognition mechanism.
This PhD project began when there were no drugs or vaccines available to efficiently treat SARS-CoV-2 infection and studies on the SARS-CoV-2 spike protein (S protein) were at their early stages. Later on, SARS-CoV-2’s Alpha, Delta and Omicron variants were spreading and little was known about their infectivity or binding patterns or their antibody-escaping. Furthermore, In light of the coagulopathy effects triggered by SARS-CoV-2 infection, the role of heparinoids was being investigated, but their mechanism was unclear and experimental observations were conflicting.
During this PhD project, I identified and evaluated potential molecular candidates for the S protein, mapped conserved cryptic binding pockets on the S protein’s stalk, characterised the S protein’s binding patterns with the angiotensin-converting enzyme (ACE2) and defined the role of heparinoids as potential allosteric regulators. For the second part of this PhD project, I proposed a promising molecular candidate against the HIV’s Negative factor protein (Nef). This manuscript will include a series of published works in which we investigated the aforementioned molecular machinery structures and proposed working hypotheses based on our results.
Date of Award | Apr 2024 |
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Original language | English |
Awarding Institution |
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Supervisor | Giuseppe Deganutti (Supervisor) & Chris Reynolds (Supervisor) |