Advertisement
The Body: The Complete HIV/AIDS Resource
Follow Us Follow Us on Facebook Follow Us on Twitter Download Our App
Professionals >> Visit The Body PROThe Body en Espanol
  
  • Email Email
  • Comments Comments
  •  (1)
  • Printable Single-Page Print-Friendly
  • Glossary Glossary
  • PDF PDF

Drug Watch: KP-1461 -- A Novel Anti-HIV Drug in Limbo?

Winter/Spring 2010

 1  |  2  |  Next > 

Table of Contents


Introduction

The path of an experimental drug from the laboratory to U.S. Food and Drug Administration (FDA) approval is typically long, rocky, and uncertain. It is especially so for a drug that turns common wisdom on its head.

Take KP-1461, a new type of antiretroviral drug from Koronis Pharmaceuticals in Seattle. Unlike all of the currently approved anti-HIV drugs, which aim to reduce the amount of virus in the body by blocking viral replication, KP-1461 was designed not to inhibit replication, but rather to force newly created HIV to become less able to infect human cells.

Despite this intriguing mechanism of action, clinical trials of the experimental drug were put on hold in 2008 due to unexpected results in laboratory studies, and they have yet to restart. The concerns were not about safety, but whether the drug is able to adequately shut down HIV production, as well as problems with recruiting trial participants. Some insiders remain optimistic about the drug, but the obstacles are substantial.

"I think that the potential is there, but we do have challenges in formulation and delivery," said Jim Mullins, PhD, researcher and key independent adviser to Koronis for the drug. "Furthermore, the virus is incredibly resilient."

Mullins, a professor of microbiology and medicine at the University of Washington in Seattle, is an expert in the area of viral mutagenesis -- in other words, how viruses mutate, or change over time. He has been studying a particular theory of viral mutation called lethal mutagenesis. If a drug like KP-1461 works as planned, it will create so many mutations in HIV's genetic code that the virus will be rendered unable to survive, replicate, and infect new cells.


Understanding Lethal Mutagenesis

Every living creature carries genetic instructions that enable it to reproduce and carry out the functions necessary to grow and sustain life. One of the strengths of viruses, including HIV, is that very little of the original genetic blueprint must be conserved from one generation to the next.

Advertisement

Another advantage is that viruses reproduce rapidly and in large numbers. This means that mutations take place quickly and many of them can occur without harming the virus population too much. Ultimately, despite the body's best attempts to control HIV, the virus mutates to overcome everything the immune system can throw at it. It also mutates to escape the effects of antiretroviral drugs, leading to drug resistance.

Mullins and others have been working on a way to turn these particular strengths into an Achilles' heel. Rather than shutting down HIV by blocking its replication or stopping mutations from occurring, the researchers hope that a drug might be used to stimulate even more mutations -- but these mutations would harm rather than help the virus.

"The idea of lethal mutagenesis really follows from the theory of what's been called 'error catastrophe,'" explained Robert Smith, PhD, an assistant research professor at the University of Washington. Simply put, the theory of error catastrophe suggests that only so many errors can be introduced into HIV's genetic blueprint before those instructions fail and the virus can no longer produce viable copies.

Under normal circumstances, numerous errors occur as HIV rapidly makes more copies of itself. In fact, a large proportion of the new virions (viral particles) created through replication are defective and incapable of infecting human cells. But because so many new virions are produced, and because so little of the viral genetic code must be conserved, the high mutation rate actually works in HIV's favor.

Experts think that all these mutations bring HIV perilously close to the error catastrophe state. If too many harmful mutations build up and the rate of error keeps increasing, the virus can lose its ability to copy itself and infect additional cells.

Carmen Ruiz-Jarabo, PhD, from Universidad Autonoma de Madrid in Spain and colleagues offered proof for this theory. In the journal Virology in 2003, they reported on the successful use of a mutagenic drug called 5-fluorouracil (5-FU) to induce lethal mutagenesis of lymphocytic choriomeningitis virus (LCMV) in mice.

The study found exactly what the theory predicted: 5-FU caused a massive increase in the mutation rate of LCMV to the point where the virus could no longer sustain itself. Similar experiments have been carried out in cell cultures of the viruses that cause polio and foot-and-mouth disease.


Enter KP-1461

The success of inducing lethal mutagenesis in other viruses sparked hope that the same result could be accomplished with HIV. In 2005, Smith published a paper in Virus Research pointing out the promise of lethal mutagenesis in HIV and describing the conditions that would have to be met by a drug designed to induce error catastrophe in this virus. He pointed to two in vitro experiments with mutagenic drugs that prompted HIV to mutate at an accelerated rate, which led to impaired replication.

According to Smith and his co-authors, one of the potential problems of a mutagenic anti-HIV drug would be the risk of causing damage to mitochondria in host cells. Mitochondria are the energy-producing powerhouses of all cells, converting fats and sugars into the energy cells need in order to function.

Several existing antiretroviral drugs in the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) class were found -- after approval -- to significantly damage mitochondria. The consequences of this mitochondrial toxicity include fat loss in the limbs, face, and buttocks (called lipoatrophy) and nerve damage that causes pain and tingling in the hands and feet (called peripheral neuropathy; see "Understanding and Managing Peripheral Neuropathy"). The data Smith reviewed suggested that an NRTI aimed at lethal mutagenesis, rather than termination of the viral life cycle, could likewise cause mitochondrial toxicity.

Also in 2005, Kevin Harris, PhD, a scientist with Koronis, published the first data on KP-1461 in Antiviral Research. The report described the potential of KP-1461, or rather its active form, KP-1212. Further down the line, Koronis found a way to boost blood levels of KP-1212 by using the body's metabolic processes to transform a small amount of the prodrug KP-1461 into a larger amount of KP-1212.

Like the NRTIs, KP-1212 has a structure similar to that of natural nucleosides, the building blocks of genetic material that exist in the body. HIV uses these building blocks to produce new DNA copies of its own genetic material. Because KP-1212 looks like a normal nucleoside, the virus can mistakenly incorporate the drug into its DNA. Given its flexible structure, it can pair up with multiple nucleoside bases, leading to mutations in the genetic code. But unlike NRTIs -- which act as defective building blocks that prevent HIV from completing new DNA strands -- KP-1212 allows the virus to continue constructing its now-mutated DNA.

Harris's team showed that in cell cultures, KP-1212 accelerated HIV's mutation rate to such a degree that it ultimately "burned out" the infection, eradicating the virus in laboratory tests.

What's more, KP-1212 did not force HIV to create drug-resistance mutations, either to itself or to any of the approved antiretroviral drugs. Instead, HIV exposed to KP-1212 became even more sensitive to that drug, as well as to approved NRTIs, including AZT (zidovudine; Retrovir) and d4T (stavudine; Zerit). Contrary to the concerns raised by Smith and his co-authors, KP-1212 also did not harm the genetic workings of host cells or mitochondria.

 1  |  2  |  Next > 


  
  • Email Email
  • Comments Comments
  •  (1)
  • Printable Single-Page Print-Friendly
  • Glossary Glossary
  • PDF PDF

This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
 
See Also
More on HIV Medications
Drugs in Development: Other New Drugs

 

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)

Your Name:


Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:

Tools
 

Advertisement