New Synthetic Molecules Trigger Immune Response to HIV And Prostate Cancer
M2 Communications
11-06-09
New Haven, Conn. - Researchers at Yale University have developed synthetic molecules capable of enhancing the body's immune response to HIV and HIV-infected cells, as well as to prostate cancer cells. Their findings, published online in the Journal of the American Chemical Society, could lead to novel therapeutic approaches for these diseases.
The molecules - called 'antibody-recruiting molecule targeting HIV' (ARM-H) and 'antibody-recruiting molecule targeting prostate cancer' (ARM-P) - work by binding simultaneously to an antibody already present in the bloodstream and to proteins on HIV, HIV-infected cells or cancer cells. By coating these pathogens in antibodies, the molecules flag them as a threat and trigger the body's own immune response. In the case of ARM-H, by binding to proteins on the outside of the virus, they also prevent healthy human cells from being infected.
'Instead of trying to kill the pathogens directly, these molecules manipulate our immune system to do something it wouldn't ordinarily do,' said David Spiegel , Ph.D., M.D., assistant professor of chemistry and the corresponding author of both papers.
Because both HIV and cancer have methods for evading the body's immune system, treatments and vaccinations for the two diseases have proven difficult. Current treatment options for HIV and prostate cancer - including antiviral drugs, radiation and chemotherapy - involve severe side effects and are often ineffective against advanced cases. While there are some antibody drugs available, they are difficult to produce in large quantities and are costly. They also must be injected and are accompanied by severe side effects of their own.
By contrast, the ARM-H and ARM-P molecules, which the team has begun testing in mice, are structurally simple, inexpensive to produce, and could in theory be taken in pill form, Spiegel said. And because they are unlikely to target essential biological processes in the body, the side effects could be smaller, he noted.
'This is an entirely new approach to treating these two diseases, which are extraordinarily important in terms of their impact on human health,' Spiegel said.
HIV is a global pandemic that affects 33 million people worldwide, while prostate cancer is the second leading cause of cancer-related death among American men, with one out of every six American men expected to develop the disease.
Funding for this research was provided by the National Institutes of Health.
CONTACT: Suzanne Taylor Muzzin, Yale University Tel: +1 203 432 8555
Here is the abstract of the American Chemical Society article
An Antibody-Recruiting Small Molecule That Targets HIV gp120
Christopher G. Parker†, Robert A. Domaoal‡, Karen S. Anderson‡ and David A. Spiegel*†‡
Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520-8107, and Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, SHM B350B, New Haven, Connecticut 06520
J. Am. Chem. Soc., 2009, 131 (45), pp 16392–16394
DOI: 10.1021/ja9057647
Publication Date (Web): October 19, 2009
Copyright © 2009 American Chemical Society
Abstract
HIV/AIDS is a global pandemic for which new treatment strategies are desperately needed. We have designed a novel small molecule, designated as ARM-H, that has the potential to interfere with HIV survival through two mechanisms: (1) by recruiting antibodies to gp120-expressing virus particles and infected human cells, thus enhancing their uptake and destruction by the human immune system, and (2) by binding the viral glycoprotein gp120, inhibiting its interaction with the human protein CD4 and preventing virus entry. Here we demonstrate that ARM-H is capable of simultaneously binding gp120, a component of the Env surface viral glycoprotein (found on the surface of both HIV and virus-infected cells) and anti-2,4-dinitrophenyl antibodies (already present in the human bloodstream). The ternary complex formed between the antibody, ARM-H, and gp120 is immunologically active and leads to the complement-mediated destruction of Env-expressing cells. Furthermore, ARM-H prevents virus entry into human T-cells and should therefore be capable of inhibiting virus replication through two mutually reinforcing mechanisms (inhibition of virus entry and antibody-mediated killing). These studies demonstrate the viable anti-HIV activity of antibody-recruiting small molecules and have the potential to initiate novel paradigms in HIV treatment.
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