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Everything that's old is new again; unique
pharmacologic class 'discovered'
Controlled trials are lacking, but one study suggests that peptide nucleic
acids may effectively battle a multitude of viruses.
[Defining peptide nucleic acids] [Developed in 1930s]
[Start with the big problems] [Repairs immune system]
[Your turn]
September 1996
NEW YORK - A discovery made during the 1930s may introduce a new
class of drugs within the next decade, said Shalom Z. Hirschman, MD.
Hirschman, director of the division of infectious diseases, Mount Sinai School of
Medicine here, and his colleague Chey Wei Chen, MD, recently published a
study suggesting that reticulose may offer a new approach to treating HIV
infection. The research was published in the August issue of the Journal of
Investigative Medicine.
Reticulose, manufactured by Advanced Viral Research Corp., is a non-toxic
peptide nucleic acid, virtually the first of its kind discovered.
Defining peptide nucleic acids
In his study, Hirschman described peptide nucleic acids as polyamide
oligomers. These oligomers combine with DNA by displacing one strand,
forming a D-loop. RNA polymerase recognizes these loops when initiating
RNA transcription. Peptide nucleic acid targets may therefore be used as
artificial promoters, or the binding method may be used to "turn off" RNA
transcription by binding the peptide nucleic acid to a specific region.
Peptide nucleic acids are remarkably stable, with a projected shelf-life of
several decades, according to Hirschman.
Developed in 1930s
"Reticulose was originally made by a physician in the mid-1930s. He essentially
synthesized a chemical structure whose existence was unknown until four years
ago," said Hirschman, who is also professor of medicine. "No one had ever
solved the chemical structure. The field of antiviral chemistry had not been
established."
The drug was developed as a treatment for mumps, but its use was expanded,
said William Bregman, secretary/treasurer for Advanced Viral Research.
Studies published in the 1950s and 1960s described the use of reticulose to
treat a variety of viral infections, such as generalized vaccinia, herpes gestationis,
herpes zoster and varicella.
Reticulose was never approved by the Food and Drug Administration (FDA).
When FDA regulations changed during the 1960s requiring that all drugs show
proof of efficacy, drugs that had been in use were exempt. Due to a "change in
a minor component" made at the time the new regulations took effect, reticulose
could not be included in the grandfather clause, Hirschman said.
Advanced Viral Research, which was established in 1984, has filed an
Investigational New Drug application with the FDA. That application is
currently on clinical hold, Bregman said.
Although he expects it will eventually be used to treat a variety of viral
infections, Hirschman's in vitro study examined the effect of reticulose on HIV
replication.
Start with the big problems
"Why did we start with HIV? It is logical," Hirschman said. "HIV is a major
problem throughout the world."
In his study, Hirschman treated peripheral mononuclear blood cells (PBMCs)
and H9 cells - a T-cell lymphoma line susceptible to, but not lysed by, HIV -
with reticulose before and after being infected with HIV.
Treatment of H9 and PBMCs with reticulose prior to HIV-1 infection resulted
in a 17% reduction in viral p24 antigen five days after infection. When newly
infected H9 cells were incubated with reticulose, however, a 69% reduction
was achieved.
Better results were achieved when the cells were pretreated by electroporation.
This process produced an 86% reduction of HIV p24 protein after five days of
incubation. HIV-1 replication was further reduced when reticulose was added
to the incubation growth medium after electroporation and inoculation of
HIV-1. Viral p24 protein decreased 92% in PBMCs and viral reverse
transcriptase activity decreased 78%.
In vitro, reticulose was compatible with zidovudine (ZDV), didanosine (ddI),
dideoxycytidine (ddC), lamivudine (3TC) and saquinavir. Combining these
drugs with reticulose, however, did not enhance the effect they have when they
are used alone.
Repairs immune system
"Our data ... indicate potential physiologic and therapeutic effects of peptide
nucleic acids," Hirschman and Chen concluded. "Reticulose ... did inhibit the
replication of HIV-1 in cell culture. This inhibition of HIV-1 does not appear to
be a direct effect of reticulose on the virus because preincubation of the viral
inoculum with peptide nucleic acids did not materially interfere with subsequent
replication of the virus. The peptide nucleic acid was active when introduced
into the cell during viral adsorption, especially under conditions favoring
transfection of nucleic acids into cells, such as electroporation. Inhibition of
HIV-1 replication was further favored by the continued presence of reticulose in
the growth medium during the incubation period."
Hirschman hypothesized that reticulose is a "powerful stimulant of many
chemokines," he told Infectious Disease News. "I gathered from all its uses that
it acts through the cell-mediated arm of the immune system and it may put the
immune system in a repair mode."
Perhaps most importantly, he said, reticulose was found to stimulate a distinct
cassette of chemokines, including interleukin-1, interleukin-6, g-interferon and
tumor necrosis factor.
If reticulose does in fact stimulate a repair of the immune system, it may provide
both cell-mediated and humoral immunity.
"Indeed, this suggests that reticulose could function as a broad antiviral drug
operating via the immune system and may in fact be useful in the therapy of
other conditions that require immune surveillance, such as neoplasias.
Furthermore, reticulose may also prove useful in repairing those conditions
where the immune system has gone awry by attacking self-proteins, such as is
seen in diseases of autoimmunity," the study concluded.
A double-blind, controlled trial is in progress, Hirschman said, with results
expected within the next few months.
"This opens up a whole class of pharmacology," he said. "It is a new world of
pharmacology. I can assure you that in the next few years, peptide nucleic acids
will be used to treat a number of viruses."
For more information see:
Hirschman S, Chen CW. Peptide nucleic acids stimulate
gamma interferon and inhibit the replication of the
human immunodeficiency virus. Journal of
Investigative Medicine 1996;44:250a.
Hanvey JC, Peffer NJ, Bisi E, et al. Antisense and
antigene properties of peptide nucleic acids. Science
1992;258:1481-85. |
