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Ribonucleoside Analogs May Be Potential New Class of HIV Drug

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A set of compounds known as ribonucleoside analogs -- related to the nucleoside/nucleotide reverse transcriptase inhibitors that currently form the backbone of combination antiretroviral therapy -- demonstrated activity against HIV in laboratory studies, halting viral replication by interrupting HIV DNA production or causing lethal mutations, according to a report in the January 2014 Journal of Virology.

Below is an edited excerpt from a University of Minnesota press release describing the research and its findings.

New Anti-HIV Drug Target Identified by University of Minnesota Researchers

December 18, 2013 -- University of Minnesota researchers have discovered a first-of-its-kind series of compounds possessing anti-human immunodeficiency virus (HIV) activity. The compounds present a new target for potential HIV drug development and future treatment options.

Complete findings are printed in today's issue of The Journal of Virology.

The compounds, known as ribonucleoside analogs 8-azaadenosine, formycin A, 3-deazauridine, 5-fluorocytidine and 2'-C-methylcytidine, were found to stop the replication and spread of HIV by blocking HIV DNA synthesis or by inducing lethal mutagenesis. Lethal mutagenesis annihilates HIV by causing it to mutate to the point of extinction.

The compound 3-deazauridine stopped HIV by creating so many mutations in the virus that the virus was no longer able to spread throughout the body by infecting other cells. The other compounds caused early termination of HIV DNA synthesis, again preventing the virus from being able to reproduce.  Studies prior to this one determined certain ribonucleosides analogs impact HIV DNA synthesis, a process called reverse transcription. The extent to which they worked was not previously known.

"It’s a counterintuitive finding," said University of Minnesota virologist Louis Mansky, PhD. "These ribonucleoside analogs were not generally thought to be associated with affecting HIV DNA synthesis -- a critical step in virus replication. We don’t yet know all the details for how these particular compounds stop the virus in its path."

The research, if translatable, will provide a potentially cost-effective and fresh treatment option to counter HIV’s rapid evolution and treat HIV resistance to currently approved anti-HIV drugs. Anti-HIV ribonucleoside analogs are less expensive to create in a laboratory than deoxyribonucleoside analogs, which are key in drugs currently used to stop HIV replication and cell spread. Additionally, the similarity of ribonucleoside analogs to deoxyribonucleosides may help speed up the development process to make full use of this target as a wealth of understanding around ribonucleoside analogs already exists.

The University of Minnesota team responsible for discovering ribonucleoside analogs with anti-HIV activity includes members from the Center for Drug Design, School of Dentistry, Institute for Molecular Virology and Masonic Cancer Center, University of Minnesota.

Funding was provided by National Institutes of Health grant nos. R01 GM56615, R21 AI96937 and T32 DA007097, as well as initial support from a University of Minnesota Center for Drug Design funding agreement. 

1/10/14

Reference

MJ Dapp, L Bonnac, ST Patterson, and LM Mansky. Discovery of Novel Ribonucleoside Analogs with Activity against Human Immunodeficiency Virus Type 1. Journal of Virology 88(1):354-363. January 2014.

Other Source

New Anti-HIV Drug Target Identified by University of Minnesota Researchers. Press release. December 18, 2013.