HIV and Drug Discovery

Having grown up and experienced the worst HIV epidemic in the early 1990, it was a childhood goal to contribute to the discovery of life saving drugs in memory of the many innocent lives that succumbed to this pandemic whilst adding a contribution on behalf of our generation to this chronic global health problem. HIV is still at large and by any means is our generational problem more so the millennials that lack first-hand experience of this notorious killer. The only validated weapon are drugs called anti-retroviral therapy whose continuous race to override a exceedingly cunning “super bug-HIV” rests upon dedicated unsung heroes (Drug discoverers) that spend many sleepless nights and long working days for the good of many. My own personal experiences led to the conjecturing of the “science for social impact phenomenon” to recapitulate these sacrifices and for the public to understand based on facts and evidence while possibly garnering more support for such revolutionary acts. Thus “Science for Social Impact” equals “Revolutionary Science”. This work was done at the Burnet Institute in HIV following upon my discovery expertise accumulated during my PhD at La Trobe University. We to discover the next generation drugs against HIV and the presentation replicates my landmark presentation at the Australian Virology Society in December 2017. I made it that, I am originally from Uganda, one of the countries worst by the epidemic. At a time it was just 4 days ago from World AIDS day which reminded us what we have to do and why we should care. Current statistics stated that HIV is still at large and it kills 2 people per minute and 3 new infections recorded in the same time frame. The big question is what really changed the once death sentence to a chronic manageable illness? These were the antiretroviral drugs which target critical HIV life cycle targets. The main ones target reverse transcriptase, an enzyme critical for HIV virus replication. These form the major backbone HIV treatment and prevention through pre-exposure prophylaxis. They are only two classes; The nucleoside/nucleotide RT active site inhibitors and the non-nucleoside reverse transcriptase inhibitors that target an allosteric site. Considering their extensive benefits, global efforts have been directed towards HIV elimination HIV by 2030, a plan underpinned by a massive global scale-up of antiretroviral therapy for both HIV treatment and prevention, a phenomenon similar to mass drug administration. Drug resistance, toxicity and an eventual exhaustion of drug options is a big threat to our eradication campaigns as we have deployed all our drug arsenal against a moving target HIV. This is a tipping point as HIV might outrun our response, keeping our patients lingering on the verge of death. Therefore, superior and timely tools are required to tide of war.
In response, we have employed a new paradigm in drug discovery called Fragment-based drug design (FBDD) to develop novel drug classes targeting reverse transcriptase a well validated target at distinctive conserved novel allosteric sites. This is to date the best approach for the job to churn out cheap, and novel drug classes compared to other approaches. It works by building drugs from small chemical units called fragments, that bind intimately bind our target efficiently. These small fragments can be expanded without compromising the original binding fragment profile. To this end, using a combination of biophysical binding and biochemical RT inhibitory assays we identified 3 inhibitory fragments that are active against circulating WT and resistant HIV strains. These hit sites distinctive allosteric sites, with modes of action distinctive to available drugs, thereby underpinning our drug discovery program. With this we can fragment-out HIV once and for all.
Dr. George Williams Mbogo
CEO BioTranslate International


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