AIDSWEEKLY Plus, 5 August 1996
Daniel J. DeNoon, Senior Editor

Human tests of the first of these new "fusion inhibitors" are scheduled for later this year, according to U.S. Food and Drug Administration (FDA) researcher Paul L. Black.

A second drug, up to a thousand times more potent, waits in the wings.

Previously known as DP-178, the drug slated for clinical trials is called pentafuside and is code-named T-20 by its manufacturer, Trimeris Inc., Research Triangle Park, North Carolina.

Animal studies of T-20 employed immunodeficient mice whose immune systems were reconstituted with human cells (the huPBMC-SCID mouse model). The animals received T-20 one day before being injected with infectious HIV.

Black presented the study findings in a presentation to the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

"T-20 dramatically reduced viral load in all the tissues, typically by 6 logs or more," Black said.

"T-20 also protected CD4 cells from HIV-induced cytopathic effects. We found that T-20 is the most effective agent we've looked at in this model."

The first peptide in the series that led to T-20 was called DP-107. This synthetic peptide was not intended to be a therapeutic agent, but instead was supposed to be a model of the difficult-to-study "coiled coil" portion (amino acids 558- 595) of the HIV gp41 transmembrane glycoprotein.

It is now known that very early in the course of HIV infection, interactions between the HIV gp120 envelope glycoprotein and the cellular CD4 receptor expose this region of gp41. This leads to a crucial step in HIV infection: the fusion of the viral envelope with the cell membrane. Once fusion occurs, the virus can inject its genetic material into the cell.

After creating DP-107, Duke University researcher Carl Wild and colleagues made the unexpected discovery that the peptide inhibited the ability of both free and cell-associated HIV to infect new cells.

Improvements on DP-107 led to the development of DP-178, now known as T-20. T-20 is a 36-mer amphipathic helical peptide which apparently blocks the transition of HIV gp41 to its fusogenic state by binding to the coiled-coil (DP-107) region of gp41.

In in vitro studies, T-20 totally blocked HIV-1-mediated cell-to-cell fusion at concentrations below 5 ng/ml. It inhibited HIV-1 at concentrations 10,000 to 100,000 times lower than cytotoxic or cytostatic concentrations.

T-20 was 10 to 1,000 times more active against HIV-1 than HIV-2, but was just as effective against primary HIV-1 isolates as it was against laboratory strains.

Preclinical pharmacokinetic studies of T-20 show that in the rat it has a rather long half life, with clinically relevant concentrations maintained for six hours. Its bioavailability following subcutaneous or intramuscular injection is 70 percent.

The extraordinary success of T-20 in the SCID mouse model of HIV infection has led to the scheduling of human trials for late 1996.

But even as human trials of T-20 begin, researchers have created an even more powerful version of the drug.

In a late-breaker poster presentation to the AIDS conference, Black announced the development of a new DP-107 analog.

"T-1052, an early-stage preclinical backup lead peptide derived from the gp41 transmembrane glycoprotein of HIV-2, shows potent and selective activity in vitro against HIV-1, HIV-2, and SIV in PBMC," Black and colleagues wrote in their poster abstract.

With an IC90 of 0.01 mg/ml, T-1052 was 100 to 1,000 times more potent than T-20 in inhibiting HIV p24 production in macrophages. T-1052 was 100-200 times more active than T-20 in preventing HIV-1 infection of PBMC.

"These results support the potential therapeutic efficacy of this novel class of antiviral agents," Black et al. concluded.

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