Viral binding inhibiting drugs

All the nearest-neighbor interactions between sialic acid or Neu5Ac2en and the protein are with totally conserved amino acids. Thus an inhibitor designed to bind only to the conserved active-site residues of neuraminidase would inhibit neuraminidase activity across all strains of influenza. This would enable the development of an antiviral drug that would affect the spread of viral replication potentially in three ways, i.e., transport through the protective mucosal layer, desialyation of freshly synthesized viral glycoproteins, and elution of progeny virions from infected cells. 

Efavirenz is a nonnucleoside reverse transcriptase inhibitor specific for HIV-1. After binding to a site distant from the active site on the HIV-1 reverse transcriptase, it disrupts catalytic activity of the enzyme by causing a conformational change and does not compete with deoxynucleoside triphosphates. Efavirenz does not inhibit HIV-2 reverse transcriptase and human DNA polymerases a, (3, 7 and 8. The resistance to the drug develops rapidly from site-directed mutagenesis specifically at codon 103, and also at codons 100, 106, 108, 181, 190 and 225 of viral reverse transcriptase. This resistance will be applicable for all nonnucleoside transcriptase inhibitors. 

Saquinavir is a peptide-like substrate analog that inhibits HIV protease after binding to its active site and is active against both HIV-1 and HIV-2 maturation. It blocks splicing of the viral polyproteins, which results in the production of immature viral particles that lack the ability to infect other cells. The resistance to saquinavir is associated with mutations in protease genes G48 V and L90 M, whereas secondary mutations are associated with codons 36, 46, 82, 84, 101, 154 and 184 multiple mutations are necessary to render strong resistance to the drug. 

Amprenavir is a nonpeptide protease inhibitor that is active against both HIV-1 and HIV-2 fosamprenavir is the prodrug for amprenavir and has better bioavailability. After binding to the active site of the viral protease, it inhibits the processing of viral gag and gag-pol polyprotein precursors, resulting in the production of immature HIV particles that lack the capability to infect other cells. The resistance to the drug results from site-directed mutagenesis primarily at codons 50 and 84, and also at codons 10, 32, 46, 54 and 90. 

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

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