398 MEDICINAL CHEMISTRY
6.3 Design of Immunomodulating Drugs
The design of new chemical entities to either stimulate or somehow modulate the immune
system represents one of the new frontiers of medicinal chemistry. The clinical indications
for such agents would be considerable, including people with immunodeficiency states
arising from cancer or chronic infections. However, this is a drug design area that is still
very much in its infancy. Serendipity has led to the identification of several compounds
with limited immunomodulating activity. For example, levamisole (6.10) is a compound
that activates macrophages, while inosiplex (6.11) augments T cell function.
Given the importance of immunomodulators, this is a drug design area that is too
important to be left to the vagaries of serendipity. The cytokines represent the best hope
for rational drug design in the area of immunomodulation.
6.3.1 Cytokines“Cytokine” is a general term used for a diverse assortment of water-soluble protein
molecules that mediate interactions between the various cells of the innate and adaptive
immune systems. Over 100 human cytokines are currently under study and more than
300,000 research papers have been published in this area over the past 10–15 years. The
interferons, discussed in section 6.2.1, are a subset of the cytokines, as are the inter-
leukins, discussed in section 6.1.3. The nomenclature used to describe cytokines is
somewhat confusing and varying subclasses of cytokines are recognized:
- Lymphokines—cytokines derived from lymphocytes
- Monokines—cytokines derived from monocytes
- Chemokines—cytokines that regulate leukocyte movement
- Interferons (IFN)—cytokines that modulate (“interfere” with) leukocyte function
- Interleukins (IL)—cytokines that mediate communication between leukocytes
- Tumour necrosis factors (TNF)—cytokines that are immunotoxic to tumors and
bacteria - Hematopoietic growth factors—cytokines that regulate proliferation of blood cells
- Granulocyte colony-stimulating factors (G-CSF)—cytokines that stimulate the
growth of granulocytic leukocytes - Macrophage colony-stimulating factors (M-CSF)—cytokines that stimulate the
growth of macrophages - Derived growth factors—cytokines that regulate proliferation of other blood
elements such as platelets (e.g., platelet-derived growth factor [PDGF])
Cytokines will act only on cells that express cytokine receptors. The classification of
cytokine receptors is also somewhat confusing. Cytokine receptors can be divided into
five broad groupings:
- Class I cytokine receptors (IL-2, IL-7, IL-9, IL-13, G-CSF)
- Class II cytokine receptors (INF-α, INF-β, INF-γ)
- Chemokine receptors (IL-8)
- TNF receptors (TNF-α, TNF-β)
- Immunoglobulin superfamily receptors (IL-1, M-CSF)