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KSHV targeted therapy: an update on inhibitors of viral lytic replication - PubMed

  • ️Wed Jan 01 2014

Review

KSHV targeted therapy: an update on inhibitors of viral lytic replication

Natacha Coen et al. Viruses. 2014.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing.

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Figures

Figure 1
Figure 1

Structures of currently approved nucleoside analogs for herpesvirus infections. Acyclovir (ACV), penciclovir (PCV), ganciclovir (GCV) are derivatives of the natural nucleoside 2’-deoxyguanosine, whereas brivudin (BVDU) is an analog of the natural nucleoside 2’-deoxythymidine.

Figure 2
Figure 2

Mechanism of action of viral DNA polymerase inhibitors against KSHV replication. Nucleoside analogs require three phosphorylation steps to become active, being their conversions to the monophosphate (MP) forms carried out by the viral TK (BVDU) or PK (ACV and GCV). Further phosphorylation to the diphosphate (DP) is carried out by the viral TK for BVDU or cellular enzymes for ACV and GCV (i.e., dGMP kinase). Conversion of these drugs to their triphosphate form (TP) by the nucleoside 5’-diphosphate (NDP) kinase results in inhibition of viral DNA polymerases because they act as competitive inhibitors of the natural substrate and/or as alternative substrates if incorporated into the growing DNA chain. ANPs, such as CDV, do not require activation by a virus-encoded enzyme to be active; instead, the two phosphorylations are done by cellular kinases (pyrimidine nucleoside monophosphate (PNMP) and 5’-diphosphate (NDP) kinase). ANP-DPs, recognized by the viral DNA polymerase, will then block DNA synthesis. PFA does not require modifications by viral or cellular kinases. PFA binds to the pyrophosphate (PPi) exchange site of the viral DNA polymerase and blocks the release of pyrophosphate from the terminal nucleoside triphosphate. As a consequence, 3’-5’-phosphodiester linkage necessary for viral DNA elongation is not possible (adapted from [62]).

Figure 3
Figure 3

Structures of ANPs that exhibit anti-herpetic activity. Cidofovir (CDV, HPMPC), HPMPA and adefovir (PMEA) belong together with (S)-HPMPDAP and PMEDAP to the first generation of ANPs. (R)-HPMPO-DAPy and PMEO-DAPy belong to the second generation of ANPs, and HPMP-5-azaC is a molecule of the third generation of ANPs.

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