AR-12: One Drug Candidate, Many Possibilities

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One Drug, Many Possibilities
A new agent may assist in the fight against HIV and other viruses
by Jeannie Wraight

[dropcap]E[/dropcap]very once in a while I come across research on a drug that may not be exactly “cure” research, but looks as though it may hold such importance that I want to include it in this column. AR-12 is one such compound.

I first became aware of this investigational agent during the poster session at the 28th International Conference on Antiviral Research in Italy this past April. This research caught my eye, as it described a compound with not only a very unique mechanism of action (the way it works) but also another very intriguing aspect to it. The drug holds the possibility of not only treating HIV, but several other viruses as well. These viruses include: influenza, Lassa, Nipah, Marburg, Ebola, measles, mumps, coxsackie, CMV, and Chikungunya.

Can you imagine in the setting of both the developed and the developing world, where one drug that could treat numerous potentially deadly viruses that affect millions of people each year? The implications of such an agent could be huge, giving clinics and doctors in rural areas a tool to combat many different viruses by keeping one medication on hand or to treat a person who has more than one virus with a single medication. Currently, AR-12 has orphan drug designation in Europe for two infectious diseases, cryptococcosis and tularaemia.

New data presented at the 2015 EU AIDS Conference (EAC) shows AR-12 could potentially be used in people who have been on numerous other HIV antiretrovirals and who have developed resistance to a number of drugs. Or it could be used in people with wild type HIV-1 or HIV-2 who are completely treatment-naïve. With many people unable to take some of the available NRTIs, NNRTIs and protease inhibitors (and thus some of the combination drugs) because of side effects or drug resistance, AR-12 could help to create a whole new drug regimen.

AR-12 is a broad-spectrum antiviral, which means, as described above, it may have an effect on numerous viruses. It works by utilizing a mechanism that no other HIV drug presently in use or in development (that I’m aware of) uses.

AR-12 is a drug originally investigated as a potential for cancer treatment and made by a small biotech company named Arno Therapeutics. Additional in vitro studies are underway to determine more about how AR-12 affects viruses, but what is known is that AR-12 works by affecting a type of chaperone protein called “heat shock” proteins. What these proteins do is assist in the folding and refolding of proteins and discarding of unusable proteins. Viruses have to hijack host cell mechanisms to produce more copies of themselves. Parts of these important steps in viral replication have been demonstrated to be dependent on various heat shock proteins. GRP78 (also known as immunoglobulin heavy chain binding protein or BiP) is a heat shock protein and is downregulated by AR-12. This creates a cascade of events that leads to the improper folding of proteins and apoptosis (cell death). Downregulation, according to an on-line source, is “the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable.” In this case, AR-12 is the external factor. AR-12 also affects other heat shock proteins such as HSP70, HSP90 and HSP27.

In the poster presented in October at the EACS Conference, data was presented which outlined AR-12’s potential use in HIV infections. Studies were conducted in peripheral blood mononuclear cells to examine the effect of AR-12 against HIV-1, HIV-2, and six drug-resistant strains. AR-12 showed an antiviral effect against all strains with AR-12 inhibiting HIV with fifty-percent inhibitory concentrations that could be achieved in patients based on the prior clinical study. The poster states: “The novel antiviral MOA of AR-12 offers a new promising approach to (1) enhance existing HIV treatments through combination therapies, (2) to circumvent existing resistance mechanisms and (3) to address co-infections with multiple viral pathogens.”

Although AR-12 has only been analyzed in vitro in regards to HIV and other viruses, it shows promise due to its unique mechanisms of actions and its potential to treat numerous illnesses that span from virus-induced cancers to various infectious diseases. As efforts continue in analyzing this drug, I hope to see further developments that will show AR-12’s potential use as a new, first-in-class drug for HIV as well as other diseases.


 

Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.