396 MEDICINAL CHEMISTRY
In addition to these small-molecule therapeutics, there are also several macromolecular
or biological therapeutics. For example, muromonab is a monoclonal antibody that blocks
antigen recognition by T lymphocytes. Infliximab is a chimereic IgG monoclonal antibody
possessing a human Fc immunoglobulin region; infliximab binds TNF-αcytokine, thus
suppressing the synthesis of IL-1 and IL-6 and therefore decreasing leukocyte activation.
However, amongst these various biological macromolecules, the interferons are those with
the most established efficacy as potential immunosuppressive therapeutics.
6.2.1 InterferonsThe interferons (IFN) are a family of cytokine molecules; cytokines are described in more
detail in section 6.3.1. Interferons are glycoproteins that can be divided into three families:
IFN-α, IFN-β, and IFN-γ. IFN-αand IFN-βare sometimes collectively referred to as Type
I IFNs because they share a 30% sequence homology in their primary amino acid struc-
ture. IFN-γis structurally separate and is a Type II IFN. Type I IFNs are acid stable; Type
II IFNs are acid labile. IFN-αis biosynthesized in lymphocytes and macrophages; IFN-β
is produced in fibroblasts, epithelial cells, and macrophages; and IFN-γis biosynthesized
in various types of lymphocyte, including CD4, CD8, and NK cells.
The effects of interferons on the human immune system are highly variable. IFN-β
tends to suppress certain aspects of immune function, whereas IFN-αcan inhibit
immune cell proliferation; IFN-γ, on the other hand, displays immune-enhancing prop-
erties. All three types of interferon have been studied preclinically and even clinically.
6.2.1.1 IFN-α
More than 24 human genes code for 16 variants of IFN-αmolecules. Human IFN-α
proteins contain either 165 or 166 amino acid residues, with an overall molecular
weight of 19,000 Da. The two primary human subtypes are IFN-α-2a and IFN-α-2b,
which differ only at position 23 (a lysine residue in IFN-α-2a and arginine in IFN-
α-2b). IFN-αtype proteins exhibit complex antineoplastic and antiviral properties.
Recombinant variants have been studied in the treatment of hepatitis C.
6.2.1.2 IFN-β
This protein tends to be somewhat unstable for routine clinical use. Accordingly, a 165-
amino acid, stable, recombinant analog of IFN-β-1b (in which a serine replaces cysteine
at position 17) is used. The IFN-βproteins have a molecular weight of 18,500 Da.
Various IFN-βproteins have been studied for the treatment of multiple sclerosis.