Attachment This phase of replication can be inhibited in two ways:
a) Using agents which mimic the V.A.P. and bind to the cellular receptor, e.g:
- anti-receptor antibodies
- V.A.P. anti-idiotypic antibodies
- natural ligands of the receptor, e.g. epidermal growth factor/Vaccinia
virus
- synthetic ligands, e.g. synthetic peptides resembling the
receptor-binding domain of the V.A.P. itself.
b) Agents which mimic the receptor and bind to the V.A.P:
- anti-V.A.P. antibodies (a natural component of the antibody response to
virus infection/vaccination)
- receptor anti-idiotypic antibodies
- extraneous receptor, e.g. rsCD4/HIV
- synthetic receptor mimics, e.g. sialic acid derivatives/influenza virus.
While the above are promising lines of experimental research, there are
considerable problems with clinical use of any of these substances. The cost of
synthetic peptides is prohibitive when the amounts required for clinically
effective whole body doses; the generation of anti-idiotypic antibodies is a
complex, poorly understood process; the pharmacokinetics of many of these
synthetic compounds is very poor.
Penetration / Uncoating It is difficult to specifically target these stages of the life cycle as
relatively little is known about them. Uncoating in particular is largely
mediated by cellular enzymes, although like penetration, is often influenced by
one or more virus proteins.
Pleconaril is a broad spectrum anti-picorna virus agent. It
is orally bioavailable and reduces peak viral titres by more than 99%; symptoms
are improved. It is a small cyclic drug which binds to a canyon pore of the
virus. In doing so it blocks attachment and uncoating of the viral particle
Amantadine and rimantadine are active
against influenza A viruses. The action of these closely related agents is
complex and incompletely understood, but they are believed to block cellular
membrane ion channels.
- The target for both drugs is the matrix protein (M2).
- Drug-treated cells are unable to lower the pH of the endosomal
compartment (a function normally controlled by the M2 gene product), a
process which is essential to induce conformational changes in the HA
protein to permit membrane fusion.
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