Ontwikkeling en SAR verkenning van nieuwe doravirine- en catechol-afgeleide hybride NNRTIs

HIV remains a global health crisis, despite decades of extensive research. A cure has yet to be found, however several drug discovery projects have resulted in the development of highly effective anti-HIV drugs, resulting in antiretroviral therapy. This therapy has become the standard of care for patients and effectively suppresses the viral load. This treatment has transformed HIV from leading to a fatal disease to a chronic illness. A particularly important target in antiretroviral therapy is the reverse transcriptase enzyme. Numerous research endeavours have aimed to inhibit this enzyme and this has led to the discovery of several NRTIs as well as NNRTIs, some of which are already approved by the FDA. Both drug classes have become integral elements of antiretroviral therapy. However, a recurrent issue in the class of NNRTIs is the emergence of drug resistance, despite some of them being very potent against WT HIV-1. Other concerns for these compounds are their suboptimal pharmacological properties, such as poor solubility, or the emergence of side effects. To adress these issues, the main goal of this project is to develop a new class of hybrid NNRTIs that combine features of the FDA approved drug doravirine and catechol-diethers, a recent class of NNRTIs that were developed through a collaboration of the research groups of Karen Anderson and William Jorgensen. With this new class of NNRTIs the aim is to achieve a compound that has an improved potency and/or a distinct resistance profile compared to existing NNRTIs. Moreover, by incorporating elements of the DOR structure a second goal is to improve the pharmacological properties.