Page 287 - Review of Medical Microbiology and Immunology ( PDFDrive )

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PART III Basic Virology
276
Inhibitors of Other Viruses
ing the viral precursor. These drugs inhibit production of
Ribavirin
infectious virions but do not affect the proviral DNA and
Ribavirin (Virazole) is a nucleoside analogue in which a
therefore do not cure the infection.
triazole-carboxamide moiety is substituted in place of the
Monotherapy with PIs should not be used because resis-
normal purine precursor aminoimidazole-carboxamide
(see Figure 35–3). The drug inhibits the synthesis of gua-
prescribed in combination with reverse transcriptase inhib-
nine nucleotides, which are essential for both DNA and
itors, such as zidovudine and lamivudine. Ritonavir is typi-
RNA viruses. It also inhibits the 5′ capping of viral mRNA. tant mutants emerge rapidly. These drugs typically are
cally used in combination with another PI, as in the
Ribavirin aerosol is used clinically to treat pneumonitis
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commonly used combination lopinavir/ritonavir (Kaletra).
caused by respiratory syncytial virus (RSV) in infants and
Ritonavir inhibits the enzymes that metabolize the other
to treat severe influenza B infections.
PI, which effectively raise the concentration of the other
“boosts” lopinavir is the way to remember it.
INHIBITION OF INTEGRASE
The side effects of PIs include nausea, diarrhea, and
Raltegravir (Isentress) is an integrase inhibitor (i.e., it
abnormal fat accumulation in the back of the neck that can
blocks the HIV-encoded integrase that mediates the inte-
result in a “buffalo hump” appearance. These abnormal fat
gration of the newly synthesized viral DNA into host cell
deposits can be disfiguring and cause patients to stop tak-
DNA). Two additional integrase inhibitors are available:
ing the drug. The fat deposits are a type of lipodystrophy;
dolutegravir (Tivicay) and elvitegravir (Stribild).
Indinavir can cause kidney stones; thus extra water should
be consumed to reduce the likelihood of stone formation.
INHIBITION OF CLEAVAGE OF the metabolic process by which this occurs is unknown.
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PRECURSOR POLYPEPTIDES
Inhibitors of Hepatitis C Virus
(PROTEASE INHIBITORS)
Boceprevir (Victrelis), simeprevir (Olysio), telaprevir
Inhibitors of Human Immunodeficiency
that block a serine protease required for the replication of
Virus
hepatitis C virus. They are approved for the treatment of
Members of the protease inhibitor (PI) class of drugs, such
chronic hepatitis C caused by hepatitis C virus (genotype 1)
as saquinavir (Invirase, Fortovase), indinavir (Crixivan),
in combination with peginterferon and ribavirin. The
ritonavir (Norvir), lopinavir/ritonavir (Kaletra), atazanavir
most important adverse effect of these drugs is anemia.
(Reyataz), tipranavir (Aptivus), amprenavir (Agenerase)
and its prodrug fosamprenavir (Lexiva), darunavir (Prezista),
able in combination with ombitsavir (an NS5A inhibitor),
and nelfinavir (Viracept), inhibit the protease encoded by
dasabuvir (a polymerase inhibitor), and ritonavir (a booster
HIV (Figure 35–5). The protease cleaves the gag and pol Paritaprevir is an inhibitor of HCV protease that is avail-
of protease inhibitor activity). This four-drug combination
precursor polypeptides to produce several nucleocapsid
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is called Viekira.
proteins (e.g., p24) and enzymatic proteins (e.g., reverse
transcriptase) required for viral replication. These inhibi-
tors contain peptide bonds that bind to the active site of the
SYNTHESIS
Interferon
H C
CH
3
3
The mode of action of interferon is described in Chapter 33.
C
O
Recombinant alpha interferon is effective in the treatment
CH
O
H
C
N
N
titis C infections. Note that the use of alpha interferon and
H
CH
C
N
C
pegylated alpha inteferon (see next paragraph) for chronic
HCV infection has been significantly reduced due to the
H
O N H O C CH 2 NH 2 C H C 2 OH 2 N H H 3 of some patients with chronic hepatitis B and chronic hepa-
availability of newer less toxic drug regimens.
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H
It also causes regression of condylomata acuminata
C
lesions caused by human papillomavirus and the lesions of
FIGURE 35–5
Structure of the protease inhibitor saquinavir.
Pegylated interferon (peginterferon), which is alpha
Note the presence of several peptide bonds, which interact with the
interferon conjugated to polyethylene glycol, is used for the
active site of the protease. An arrow indicates one of the peptide
treatment of chronic hepatitis B and C. The advantage of
bonds.
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