Researchers discover virus cycle drug target

Related tags Virus Antiretroviral drug Hiv

An opportunity to develop drugs by targeting a recently discovered,
and potentially vulnerable, intermediate stage of the viral life
cycle, could result in a new pharmaceutical treatment in the fight
against HIV and other similar microbes.

The researchers discovered that once the virus fuses with the host cell membrane the pore through which the virus unloads its genetic cargo into the host cell does not open up right away. Instead, a small pore opens for several minutes before adopting its final size, or (in rare cases) closing permanently.

This 'intermediate stage,' is this time interval and was not known to exist for virus-cell fusion events previously. The overall effect is that the invading virus is held up for an amount of time and, in the rare cases in which the pore does not open, it fails to infect the cell at all.

This phenomenon is causing much excitement within the research team because even a brief pause during the process by which a virus invades a cell provides a possible new drug target in the fight against HIV and other similar microbes.

This latest discovery is an apparent u-turn over what previous research has been saying. Scientists had always assumed that once a virus begins fusing with a cell's membrane, infection of the host cell was inevitable.

Thus, strategies in antiviral drug development have largely focused on preventing events that happen either before or after this step. Indeed, any of the stages of viral replication can be a target for antiviral intervention.

The only requirements are, that the process targeted be essential for virus replication and that the therapeutic agent is active against the virus while having "acceptable toxicity" to the host organism

Antiviral drugs currently on the market include Vidarabine, a treatment for Herpes viruses. This nucleoside analogue targets the enzyme virus polymerase.

HIV treatments include nucleoside-analog reverse transcriptase inhibitors (NRTI) such as AZT (Zidovudine), ddI (Didanosine), ddC (Zalcitabine), d4T (Stavudine) and 3TC (Lamivudine). These drugs specifically target the retroviruses (HIV) specifically focusing on the reverse transcriptase enzyme.

A similar treatment is the protease inhibitors, Saquinavir, Ritonavir, Indinavir and Nelfinavir. This treatment specifically targets the HIV protease enzyme

The remarkable findings were published by the Proceedings of the National Academy of Sciences​ online on June 3 in which individual viruses such as Avian sarcoma and leukosis virus (ASLV), a disease that is in the same class as HIV was used in the study.

"It's like a space craft docking on a space station,"​ said microbiologist John Young of the Salk Institute for Biological Studies.

"If you try to open the inner door before the pressures have equalised, you can tease it open a little bit but it keeps closing on you until there's enough pressure in the airlock to allow it to open all the way,"​ he added.

Biophysicist Gregory Melikyan of Rush University Medical Centre in Chicago added: "The pore is an unstable structure at that moment: some pores will open and some won't. It's a crucial point in viral entry because it's critical for the pore to enlarge sufficiently for the genetic material to pass into the host cell."

Melikyan said that the model is likely to apply to any virus such as HIV that fuses with the cell membrane and shares the same fusion proteins, providing a new target. Also, existing drugs can be re-evaluated to pinpoint at what stage they actually work, to fine-tune their activity.

The next stage is for researchers to confirm that other viruses such as HIV also have an intermediate step. Preliminary data from the Melikyan laboratory indicate that this may be the case for HIV.

"We already know that the entire HIV fusion sequence is very slow, sometimes taking several hours,"​ said Melikyan. "It is not inconceivable that it, too, has an intermediate step that lasts several minutes, giving us an adequate time window for drug action."

Related topics Preclinical Research Ingredients

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