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Nov 6, 2009

Researchers Design Molecules that Trigger Immune Response to HIV and Prostate Cancer

  • 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 prostate cancer cells. They work by binding simultaneously to an antibody already present in the bloodstream and to proteins on HIV and HIV-infected cells or cancer cells.

    “Instead of trying to kill the pathogens directly, these molecules manipulate our immune system to do something it wouldn't ordinarily do,” explains David Spiegel, M.D., assistant professor of chemistry.

    Dr. Spiegel is also the author of two separate papers appearing in the Journal of the American Chemical Society that detail the findings: “An Antibody-Recruiting Small Molecule That Targets HIV gp120” and “Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer”.

    The molecules are called antibody-recruiting molecule targeting HIV (ARM-H) and antibody-recruiting molecule targeting prostate cancer (ARM-P). 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. ARM-H has the potential to interfere with HIV survival through two mechanisms: by recruiting antibodies to gp120-expressing virus particles and infected human cells, thus enhancing their uptake and destruction by the human immune system, and by binding the viral glycoprotein gp120, inhibiting its interaction with the human protein CD4 and preventing virus entry.

    The scientists were able to 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, which are present in the human bloodstream. The ternary complex formed between the antibody, ARM-H, and gp120 was immunologically active and led to the complement-mediated destruction of Env-expressing cells.

    Furthermore, ARM-H prevented 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.

    In the second study related to prostate cancer, ARM-P derivatives were designed rationally via the computational analysis of crystallographic data. The investigators showed that these materials are able to bind prostate-specific membrane antigen (PSMA) with high affinity, template the formation of ternary complexes of anti-DNP antibodies, ARM-P, and LNCaP human prostate cancer cells, as well as mediate the antibody-dependent killing of LNCaP cells in the presence of human effector cells.

    The ARM-H and ARM-P molecules, which the team has begun testing in mice, are structurally simple, inexpensive to produce, and could be an oral treatment, according to Dr. Spiegel. And because they are unlikely to target essential biological processes in the body, the side effects could be smaller, he notes.

     



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