Talk Summary by Sam van Druten
Viruses are a prevalent topic of discussion nowadays. I thought it would be interesting to watch the Varsity Sci talks on virology to help me understand the subject better, and to help distinguish between the fake news and real facts making their way through the media.
I was grateful that I did, because Phuong Pham’s talk on a new class of HIV drugs known as HIV-1 maturation inhibitors (MIs), the subject of her PhD project, actually gave some hopeful news on virus treatment. Unlike protease inhibitors, which bind the enzymes that cleave group antigen (Gag) polyproteins to produce viral core proteins, MIs disrupt the processing of Gags by binding the Gags themselves. An example of this is Bevirimat, which binds the polyprotein produced by the expression of the HIV genome at the SP1 region of the capsid (CA-SP1). By binding to this region, it blocks the appropriate protease from cleaving the structural polyprotein, preventing the virion particles generated from becoming infectious.
Despite appearing initially promising, Bevirimat did not make it past Phase II clinical trials, during which around 50% of the patients were unresponsive to the drug. This was due to certain polymorphisms (differences in the sequences of DNA) within the SP1 region which the drug targets, most notably a valine to alanine mutation at position 7, referred to as SP1-V7A.
In response to this, Pham and her colleagues aimed to develop Bevirimat analogues that more effectively inhibit HIV-1 replication and display broader activity against viral strains with these SP1 polymorphisms. In theory, the compounds they created would dock at the target region despite mutations being present, which would allow them to stabilise the immature Gag lattice and, as before, prevent the protease from coming to the site.
Over 500 analogues were synthesised, and it was found that changes made at carbon 28 of the Bevirimat structure made the second-generation MIs more potent with respect to their parent analogue. A specific screen of ten of their new compounds against both wild type and the SP1-V7A mutant suggested that these compounds were able to block virus activity in both types of virus as measured by a high level of accumulation at the SP1 site in accumulation assays. Furthermore, an analysis of IC50 values, a measure of potency, suggested that the second-generation compounds were about 50 times more potent than Bevirimat itself.
Similarly, in cell cultures, they noticed that these compounds were able to inhibit virus replication, resulting in roughly a 3-week delay in the viral particle number peaking. They then sequenced the virus to see which mutations had arisen during the drug selection process. This revealed that selection for resistance gave rise to mutations in highly conserved regions of the viral genome (sequences which have remained relatively unchanged in evolution), including in the capsid major homolog region in HIV subtype B, the subtype of HIV more prevalent in Europe, as well as in subtype C, that more prevalent in Africa.
Overall, Pham and her colleagues have successfully identified a set of C-28 alkyl amine derivatives of Bevirimat that exhibit activity across major clades of HIV-1 at low concentrations, even strains of the virus that have reduced susceptibility to Bevirimat, and some with new mutations. The next stage of their research involves testing on more patient samples. Currently, their compound is entering Phase IIb trials. If these novel MI compounds pass the clinical trials, similar compounds could perhaps be applied to create novel drugs for treating other viruses (including coronaviruses) given the importance of the maturation stage in their lifecycles.
This article gives a report of the talk ‘Potent and broadly active HIV-1 maturation inhibitors’ given by Phuong Pham on the 21st of September- Day 1 of the Oxbridge Varsity Sci symposium.