DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

A B1
uncoating
nucleus
1
golgi
3
glycoproteins
assembly
B2
2
proteins
4
Viruses
A. DNA
B. RNA
1. orthomyxoviruses and retroviruses
2. picornaviruses and most RNA viruses
IFN Effects
1 inhibition of transcription
activates Mx protein
blocks mRNA synthesis
2 inhibition of translation
activates methylase, thereby reducing
mRNA cap methylation
activates 2’5’ oligoadenylate synthetase
2’5’A inhibits mRNA splicing
and activates RNaseL cleaves
viral RNA
activates protein kinase P1 blocks
eIL-2a function inhibits initiation
of mRNA translation
activates phosphodiesterase
tRNA function
blocks
3 inhibition of post-translational processing
inhibits glycosyltransferase, thereby reducing
protein glycosylation
4 inhibition of virus maturation
inhibits glycosyltransferase, thereby reducing
glycoprotein maturation
1611
CHAPTER 58
ANTIVIRAL AGENTS (NONRETROVIRAL)
5
release
5 inhibition of virus release
causes membrane changes
budding
blocks
Figure 58–5. Interferon-Mediated Antiviral Activity Occurs via Multiple Mechanisms. The binding of IFN to specific cell surface receptor molecules
signals the cell to produce a series of antiviral proteins. The stages of viral replication that are inhibited by various IFN-induced antiviral
proteins are shown. Most of these act to inhibit the translation of viral proteins (mechanism 2), but other steps in viral replication also are
affected (mechanisms 1, 3, and 4). The roles of these mechanisms in the other actions of IFNs are under study. Key: IFN = interferon; mRNA
= messenger RNA; Mx = IFN-induced cellular protein with anti-viral activity; tRNA = transfer RNA; RNase L = latent cellular endoribonuclease;
2′5′A = 2′-5′-oligoadenylates; eIF-2α = protein synthesis initiation factor. (Modified from Baron et al., 1992, with permission.)
containing an IFN-specific response element. This, in
turn, leads to synthesis of over two dozen proteins that
contribute to viral resistance mediated at different stages
of viral penetration (Samuel, 2001) (Figure 58–5).
Inhibition of protein synthesis is the major inhibitory effect
for many viruses. IFN-induced proteins include 2′-5′-oligoadenylate
[2-5(A)] synthetase and a protein kinase, either of which can inhibit
protein synthesis in the presence of double-stranded RNA. The
2-5(A) synthetase produces adenylate oligomers that activate a latent
cellular endoribonuclease (RNase L) to cleave both cellular and viral
single-stranded RNAs. The protein kinase selectively phosphorylates
and inactivates a protein involved in protein synthesis, eukaryotic
initiation factor 2 (eIF-2). IFN-induced protein kinase also may
be an important effector of apoptosis. In addition, IFN induces a
phosphodiesterase that cleaves a portion of transfer RNA and thus
prevents peptide elongation. A given virus may be inhibited at several
steps, and the principal inhibitory effect differs among virus
families. Certain viruses are able to counter IFN effects by blocking
production or activity of selected IFN-inducible proteins. For example,
IFN resistance in hepatitis C virus is attributable to inhibition of
the IFN-induced protein kinase, among other mechanisms.
Complex interactions exist between IFNs and other parts of the
immune system, so IFNs may ameliorate viral infections by exerting
direct antiviral effects and/or by modifying the immune response to infection
(Biron, 2001). For example, IFN-induced expression of MHC antigens
may contribute to the antiviral actions of IFN by enhancing the lytic
effects of cytotoxic T-lymphocytes. Conversely, IFNs may mediate some
of the systemic symptoms associated with viral infections and contribute
to immunologically mediated tissue damage in certain viral diseases.