Development and SAR exploration of novel doravirine- and catechol-derived hybrid NNRTIs

Promovendus/a: Eline Goffin

Promotor(en): Prof. dr. Peter Verwilst

Since HIV was first identified in the 1980s, it has affected millions of lives around the world. While there’s still no cure, modern treatments, especially antiretroviral therapy (ART), have turned HIV from a deadly disease into a manageable condition.

One important group of HIV medicines is called non-nucleoside reverse transcriptase inhibitors (NNRTIs). These drugs help block the virus from copying its genetic material into DNA, a readible form of genetic material that can be incorporated into our genome and by doing so, they block further infection. Although several NNRTIs are already approved and in use, they can lose effectiveness over time due to drug resistance, side effects, or other limitations. That’s why scientists are still working hard to develop new or improved versions.

This PhD project focused on designing and testing a new type of NNRTIs that could overcome some of these challenges. The research began by creating a new chemical structure inspired by two existing drugs. After testing different ways to synthesize this compound in the lab, the first compounds were produced and tested against HIV. Unfortunately, most of them didn’t work well, likely because the molecules were too flexible to fit properly into the enzymatic target.

To improve this limitation, the structure was made more rigid, and this led to a promising new compound that showed strong activity against HIV. Further tweaks to the structure improved its effectiveness and resistance to viral mutations. However, some of these improved compounds still had issues, like poor solubility in water.

In the final stage of the research, new versions similar to the previous structures but with specifically altered chemical groups to improve both solubility and effectiveness were made and tested. Several of these new compounds performed well, showing that this new chemical design has real potential for future HIV treatments.