Human immunodeficiency virus (HIV) remains a global health problem. While combined
antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance
to drugs used for treatment, rendering available drugs less effective and limiting treatment options.
Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus
on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches
tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in
antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in
patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based
drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight
molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds,
but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based
strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse
transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives
against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search
for novel classes of HIV-1 drugs.
Keywords: Antiretrovirals, HIV-1, Fragment-based drug discovery, Reverse transcriptase, Integrase, Fragment screening.
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