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Using SCOPE to Identify Potential Regulatory Motifs in Coregulated Genes
Published on: May 31, 2011
Sixty Years at the Rega Institute
1Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Insights
This research highlights the discovery of key antiviral compounds, including interferon inducers and reverse transcriptase inhibitors, leading to treatments for HIV and Hepatitis B virus infections.
Area of Science:
- Virology
- Immunology
- Medicinal Chemistry
Background:
- Interferon research began with polyacrylic acid (PAA) and Poly(I)·Poly(C) as inducers.
- The discovery of reverse transcriptase (RT) spurred the search for inhibitors.
- Early HIV replication inhibitors included suramin and nucleoside analogs.
Purpose of the Study:
- To identify potent inducers of interferon and inhibitors of viral replication.
- To develop effective treatments for Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV).
- To explore novel antiviral agents, including nucleoside and non-nucleoside reverse transcriptase inhibitors.
Main Methods:
- Identification of interferon inducers like PAA and Poly(I)·Poly(C).
- Screening for reverse transcriptase inhibitors, leading to the discovery of suramin.
- Development and testing of acyclic nucleoside phosphonates and non-nucleoside RT inhibitors (NNRTIs).
Main Results:
- Cloning and expression of human β-interferon.
- Suramin identified as the first HIV replication inhibitor.
- Discovery of potent acyclic nucleoside phosphonates and NNRTIs for HIV and HBV.
- Tenofovir emerged as a key nucleotide RT inhibitor, with prodrugs TDF and TAF developed.
Conclusions:
- Significant advancements in antiviral drug discovery for HIV and HBV.
- Development of effective therapies including nucleotide RT inhibitors and their prodrugs.
- Efficacy of these drugs in Pre-Exposure Prophylaxis (PrEP) for HIV prevention.
Abstract:
I started my research career (in 1965) on interferon by identifying polyacrylic acid (PAA) as an interferon inducer. Poly(I).poly(C), discovered by Maurice Hilleman's group, proved to be more potent as an interferon inducer, and through its mRNA, we were able to clone and express human β-interferon. The discovery of the reverse transcriptase (RT) by Temin and Baltimore (in 1970) brought me to the detection of suramin as a powerful RT inhibitor and enabled Sam Broder and his colleagues to identify suramin as the first inhibitor of HIV replication. In this capacity, it was subsequently superseded by AZT and other 2',3'-dideoxynucleoside (ddN) analogs, including d4T. In collaboration with Antonín Holý, we discovered several acyclic nucleoside phosphonates as potent inhibitors of both HIV and HBV (hepatitis B virus) replication. In collaboration with Paul Janssen, we identified various non-nucleoside RT inhibitors (NNRTIs) of HIV-1 replication. Of the nucleotide RT inhibitors (NtRTTs), tenofovir emerged as the most promising congener. It was derivatized to its oral prodrugs TDF and TAF. To enhance their efficacy, they were combined with other anti-HIV drugs, and two of them were pursued (and found efficacious) in the Pre-Exposure Prophylaxis (PrEP) of HIV infections.
