Inhibiting Viral Binding

Enfuvirtide requires parenteral administration, and the peak levels are reached in about 4 h. Its bioavailability is 84%, and the drug is 92% protein-bound in plasma. Its half-life is 3.8 h, and enfuvirtide is metabolized in liver, which is not at significant levels. Enfuvirtide is approved for the treatment of HIV in patients whose response to antiretroviral therapeutic regimen is not satisfactory, and there is indication that HIV is still replicating. 

Irritation at the site of injection is a common problem that may include pain, swelling, redness and induration nodules or cysts at the site of injection have also been reported. No drug interactions are known. 

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In addition to inhibiting viral binding, dendrimers have been shown to exhibit the ability to disturb the replication of viruses. Amine-terminated PAMAM dendrimers have been reported to interact with transacting response elements RNA, which affected the viral replication.[156] Moreover, viral protease and reverse transcriptase were inhibited by carboxylated fullerene-based dendrimers and sulfonated dendrimers, respectively.[157]... 

It appears that polyoxometalates are active at the cell surface (354, 355), and they exhibit anti-HIV activity by binding to viral envelope sites (356, 357), interfering with virus adsorption (358). They also inhibit the binding of HIV-l-infected lymphocytes to uninfected lympho-... 

Interferons are natural proteins produced by the cells of the immune system in response to challenges by foreign agents such as viruses, parasites and tumor cells. Interferons assist the immune response by inhibiting viral replication within host cells. There are three major classes of interferons, interferon type I, interferon type II and interferon type III. They bind to a differen cell surface receptor complexes. The type I interferons in humans are IFN-o , IFN-jS and IFN- >. IFN-y is human interferon type II. All classes of interferon are important in fighting RNA virus infections and endogenous interferons are secreted when abnormally large amounts of dsRNA are found in a cell. 

The NNRTIs inhibit viral reverse transcriptase by binding adjacent to its active site and inducing a conformational change that causes the enzyme s inactivation. When combined with NRTIs or protease inhibitors,... 

Mectianism of Action An immunomodulator that binds to specific membrane receptors on the cell surface, inhibiting viral replication in virus-infected cells, suppressing cell proliferation, and producing reversible decreases in leukocyte and platelet counts. Therapeutic Effect Inhibits hepatitis C virus. 

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog (Figure 49-2) that inhibits viral DNA polymerase, RNA polymerase, and HIVreverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV-1. 

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49-4). Each requires intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1. 

The idea that an inhibitor that binds to a nonenzymatic, nonreceptor site of a virion could inhibit viral replication in vivo would a priori be considered to be an unlikely scenario by most in the field of stmcture-based design. If this idea were proposed knowing only the structure of the native vims (especially HRV14, which has a closed-pocket conformation) skepticism would abound. This type of project arose not from a stmcture-based approach, but from the tried-and-tme screening approach. The compounds were first shown to be effective in inhibiting viral replication in vitro [52]. This was followed by an experiment showing that these compounds could inhibit at least one enterovims in a mouse model [94]. 

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by the host s cellular enzymes (Figure 49-3). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms competitive inhibition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex and chain termination following incorporation into the viral DNA. 

C-sialyl moieties into liposomes showed excellent inhibition of viral binding.28 For practical applications, such moieties have also been integrated into molecular scaffolds for identifying GlcNAc 6-O-sulfotransferase activity specific to lymphoid tissue.29... 

Vitravene binds the mRNA sequences containing the CMV major immediate early region 2 (IE2), which encodes several protein-regulating expression of genes essential to CMV production. Vitravene binding inhibits IE2 protein synthesis, thus inhibiting viral replication. 

The type-V glycopeptide antibiotics with complestatin or chloropeptin as representatives show no antibacterial activity. Instead, the inhibition of binding of viral glycoprotein gpl20 to cellular CD4-receptors was found. Characteristic features for this subclass are a DE-biaryl ring, which is formed by 4-hydroxyphenylglycine (AA4) and tryptophan (AA2). 

A non-natural glycosphingolipid inhibited caveolar uptake, viral binding and infectivity, and 31-integrin signaling... 

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