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MEDICINAL CHEMISTRY
and is heavily dependent upon the actions of cytokines—molecular messengers that
coordinate the activities of the various types of lymphocytes.
T cells and B cells are the centerpiece of adaptive immunity. When an unwanted protein or molecule has successfully evaded the innate immune system, a macrophage, acting as an antigen-presenting cell (APC), enzymatically digests part of the unwanted
protein and then attaches the resulting peptide fragments to a surface protein, called a
Class II MHC (major histocompatibility complex) protein; this attachment process is
facilitated by adhesion molecules (e.g., ICAM-1). The resulting processed “antigenic peptide fragment–class-II MHC surface protein” complex forms a macromolecular assembly
that is then “presented” to a circulating subtype of T cell called a T helper cell or a T H cell.
These activated T H cells secrete a cytokine molecule (interleukin-2, IL-2), which triggers
activation and proliferation of two new classes of lymphocytes, called T H 1and T H 2 cells.
The T H 1 cells then produce two additional cytokines (interferon-γ [IFN-γ]; tumor necrosis factor-β [TNF-β]), which activate two additional classes of leukocytes (activated
natural killer cells [NKs]; activated cytotoxic T cells [CTLs]). The NK and CTL cells then
attack and kill the unwanted intruder cell; in addition, the NK cells produce another
messenger molecule, called a lymphokine, which activates a group of “promiscuous killer
cells,” called lymphokine-activated killer (LAK) cells. While the T H 1 cells are initiating
this complex cascade, the T H 2 cells are concomitantly producing two different cytokine
molecules (interleukin-4 [IL-4] and interleukin-5 [IL-5]). IL-4 and IL-5 then establish
a molecular interface with the B-cell lymphocyte system. IL-4 and IL-5 induce the
proliferation and differentiation of B-cell lymphocytes, resulting in the increased production of antibody immunoglobulins. As discussed above, the immunoglobulins “set up”
the unwanted cellular intruder for attack and removal by neutrophils and phagocytic
macrophages. A further level of fine-tuning is imposed on this immune cascade by one
additional cytokine molecule (interleukin-10, IL-10), which mediates a feedback control
loop between the T H 1 and T H 2 subsets of cells.
Since the immune system exerts a major influence upon inflammation in the body,
drug design that targets immunocompetent systems would appear to have many useful
applications. Logically, drug design that targets immune messengers and their receptors
can be divided into three broad groupings:
1. Immunosuppressive agents
2. Immunostimulating agents
3. Immunomodulating agents
A survey of the relatively small number of drugs available for influencing the immune
system reveals that the majority of them are immunosuppressive agents. Clearly, this is
an area of medicinal chemistry with immense potential for growth and innovation. As the
various cytokine messengers and their receptors become better understood, important
opportunities for drug design will emerge.
6.2 DESIGN OF IMMUNOSUPPRESSIVE DRUGS
Logically, immunosuppressive drug design can be divided into five main categories:
1. Agents (“small” molecules) that inhibit lymphocyte proliferation
“Nonspecific” cytotoxic agents
MEDICINAL CHEMISTRY
and is heavily dependent upon the actions of cytokines—molecular messengers that
coordinate the activities of the various types of lymphocytes.
T cells and B cells are the centerpiece of adaptive immunity. When an unwanted protein or molecule has successfully evaded the innate immune system, a macrophage, acting as an antigen-presenting cell (APC), enzymatically digests part of the unwanted
protein and then attaches the resulting peptide fragments to a surface protein, called a
Class II MHC (major histocompatibility complex) protein; this attachment process is
facilitated by adhesion molecules (e.g., ICAM-1). The resulting processed “antigenic peptide fragment–class-II MHC surface protein” complex forms a macromolecular assembly
that is then “presented” to a circulating subtype of T cell called a T helper cell or a T H cell.
These activated T H cells secrete a cytokine molecule (interleukin-2, IL-2), which triggers
activation and proliferation of two new classes of lymphocytes, called T H 1and T H 2 cells.
The T H 1 cells then produce two additional cytokines (interferon-γ [IFN-γ]; tumor necrosis factor-β [TNF-β]), which activate two additional classes of leukocytes (activated
natural killer cells [NKs]; activated cytotoxic T cells [CTLs]). The NK and CTL cells then
attack and kill the unwanted intruder cell; in addition, the NK cells produce another
messenger molecule, called a lymphokine, which activates a group of “promiscuous killer
cells,” called lymphokine-activated killer (LAK) cells. While the T H 1 cells are initiating
this complex cascade, the T H 2 cells are concomitantly producing two different cytokine
molecules (interleukin-4 [IL-4] and interleukin-5 [IL-5]). IL-4 and IL-5 then establish
a molecular interface with the B-cell lymphocyte system. IL-4 and IL-5 induce the
proliferation and differentiation of B-cell lymphocytes, resulting in the increased production of antibody immunoglobulins. As discussed above, the immunoglobulins “set up”
the unwanted cellular intruder for attack and removal by neutrophils and phagocytic
macrophages. A further level of fine-tuning is imposed on this immune cascade by one
additional cytokine molecule (interleukin-10, IL-10), which mediates a feedback control
loop between the T H 1 and T H 2 subsets of cells.
Since the immune system exerts a major influence upon inflammation in the body,
drug design that targets immunocompetent systems would appear to have many useful
applications. Logically, drug design that targets immune messengers and their receptors
can be divided into three broad groupings:
1. Immunosuppressive agents
2. Immunostimulating agents
3. Immunomodulating agents
A survey of the relatively small number of drugs available for influencing the immune
system reveals that the majority of them are immunosuppressive agents. Clearly, this is
an area of medicinal chemistry with immense potential for growth and innovation. As the
various cytokine messengers and their receptors become better understood, important
opportunities for drug design will emerge.
6.2 DESIGN OF IMMUNOSUPPRESSIVE DRUGS
Logically, immunosuppressive drug design can be divided into five main categories:
1. Agents (“small” molecules) that inhibit lymphocyte proliferation
“Nonspecific” cytotoxic agents