In brief

Targeting an alternative subunit of a key replicative enzyme of the human immunodeficiency virus (HIV) could help prevent drug resistance. 3D structure of the p66 and p51 subunits of the HIV reverse transcriptase enzyme showing a known drug binding site (blue) and an alternative target (red).

© Chinh Tran To Su

A new approach to an old pandemic

6 Jul 2021

The discovery of a new, highly conserved druggable site on the HIV reverse transcriptase could turn the tide in the wake of growing drug resistance.

It’s easy to forget that COVID-19 isn’t the only pandemic currently sweeping over the world. Though the World Health Organization calls it a ‘global epidemic,’ HIV has been around in humans for almost half a century—taking the lives of at least 33 million people since its discovery and infecting countless more.

Until today, HIV cannot be cured, but it can be managed using medications that disrupt various stages of the life cycle of the virus. Some, for example, attack the reverse transcriptase (RT) enzyme which HIV needs for genetic replication. As its name implies, RT converts HIV RNA to DNA, which then integrates into the host’s genome. However, because the virus can mutate at a frightening rate, it can also quickly develop drug resistance, eventually rendering most therapies against it weak or useless.

Though previous drug development efforts focused on HIV-1 RT’s catalytic p66 subunit, research led by Samuel Gan, Senior Principal Investigator at A*STAR’s Experimental Drug Development Centre (EDDC) and Bioinformatics Institute (BII) found an alternative approach. After a series of computational analyses with Peter Bond, Senior Principal Investigator at BII, experiments confirmed potential chemical compounds that could bind to RT’s other subunit, p51.

When used on whole intact RT containing both p66 and p51, the researchers observed that increasing concentrations of the novel compound managed to inhibit the conversion of RNA into DNA. However, when working with p66 alone, the reverse transcription polymerase chain reaction proceeded normally, producing signals from the amplified DNA.

To better visualize the interaction between p51 and the novel compound, the team performed molecular dynamic simulations, seeing strong binding potential at residue Y183. Intriguingly, no drug resistance mutations have been documented at Y183 so far, with the surrounding binding region found to also be highly conserved across different viruses that use the RT enzyme.

Together, their findings provide proof-of-concept that targeting p51 can disrupt the HIV-1 RT through a previously unexplored, indirect mechanism—opening up new possibilities for overcoming drug resistance in the fight against HIV and other viruses. “Given that the druggable site we found is conserved across viral RTs, it is likely to be more conserved and with less changes, meaning lower drug resistance,” Gan explained.

Because RT is present only in viruses, finding fresh ways to target the enzyme also paves the way for safer antivirals for vulnerable populations like young children or pregnant women. Towards this goal, Gan and his team are planning to find better scaffolds and bring the project forward in China with a company and HIV research center in Beijing.

The A*STAR-affiliated researchers contributing to this research are from the Experimental Drug Development Centre (EDDC), Bioinformatics Institute (BII) and p53 Laboratory.

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Chan, K.F., Su, C.T.T., Krah, A., Phua, S.X., Yeo, J.Y. et al. An alternative HIV-1 non-nucleoside reverse transcriptase inhibition mechanism: Targeting the p51 subunit, Molecules 25, 5902 (2020) | article

About the Researcher

Samuel Gan was the Senior Principal Investigator at the Antibody and Product Development Lab of A*STAR and is adjunct Associate Professor at James Cook University Singapore (JCUS). Gan’s cross-disciplinary research interests include antibody engineering and virus drug resistance for sagacious drug design. He has been recognised as one of the “World’s Most Promising Researchers” in the Interstellar Initiative by the New York Academy of Sciences and the Japan Agency for Medical Research and Development, as well as one of the 30 world class fusion innovators in the book “Innovation Through Fusion” by SP Jain School of Global Management. He is also the Bronze winner of the inaugural Merck Lab Connectivity Challenge 2020, and the 2021-22 “Science and Sustainability” category of the UK Alumni Awards, Singapore.

This article was made for A*STAR Research by Wildtype Media Group