Medicinal Chemistry

390 MEDICINAL CHEMISTRY

Monocytes.After the lymphocyte-initiated killing is over, the resulting cellular
debris is cleaned up by another important phagocytic cell called a macrophage.The
macrophage is derived from the circulating agranular leukocyte called a monocyte. In
recent years, the immunological importance of monocytes and macrophages has been
more greatly appreciated.

6.1.1.2 Granular Leukocytes

Granular leukocytes are the dominant leukocytes. They are heavily involved with the
killing of unwanted intruder cells, and are of many types.

Neutrophils.Neutrophilsare the main type of granulocyte and are the predominant
circulating white blood cell of the human body. Neutrophils work in close harmony with
lymphocytes; in fact, T lymphocytes, upon being activated through an interaction with
an antigen, release chemical messengers (chemotactic factors) to attract both B lympho-
cytes and neutrophils to the site of the immune response. This process is referred to as
chemotaxis.Immunoglobulins, produced by B lymphocytes, bind to the “unwanted”
antigen via the F(ab) 2 end of the antibody molecule, leaving the Fc end of the molecule
exposed and free; the neutrophil possesses a surface receptor to recognize this Fc por-
tion of the antibody molecule, to which it then binds. In turn, this leads to the creation
of a neutrophil–antibody–antigen–unwanted cell complex. The neutrophil then kills the
unwanted cell by the process of phagocytosis, in which the foreign substance (for
example, a bacterium) is literally engulfed by the neutrophil—completely “swallowed”
via a membrane-bound sphere called a vacuole.Once the vacuole is engulfed, enzyme-
containing bodies (called phagolysosomes) contained within the neutrophil fuse with the
vacuole and release their destructive enzymes, leading to the death of the unwanted cell.

Basophils and Eosinophils. These two types of granulocyte represent only a small
proportion of the circulating leukocytes. The basophil possesses receptors specific for
the Fc portion of IgE molecules. It is involved in allergic reactions and can play a role
in the clinical state of anaphylaxis, which is a life-threatening allergic response.
Eosinophils are involved with the immune reactivity of drug allergies and with the
body’s immune response to parasitic infestations such as worms (see chapter 9).
These diverse cellular constituents of the immune system provide protection and
repair within the body by two principal components: the innate and the adaptive
immune systems. From a functional perspective, these two immunological systems are
crucial to the process of future drug design.

6.1.2 The Innate Immune System

The innate immune system constitutes the front line of defense against disease and has
three structural components:

1. Histological (at the tissue level) defense systems (e.g., skin)


2. Cytological (at the cellular level) defense systems (e.g., macrophages, neutrophils)


3. Biochemical (at the molecular level) defense systems (e.g., complement proteins)