Design and Syntheses of 1,6-Naphthalene Derivatives as Selective HCMV Protease Inhibitors

Gopalsamy, Ariamala; Lim, Kitae; Ellingboe, John W.; Mitsner, B. I.; Nikitenko, A. A.; Upeslacis, Janis; Mansour, Tarek S.; Olson, Matthew W.; Bebernitz, Geraldine; Grinberg, Diane; Feld, Boris; Moy, Fred; O’Connell, John F.

doi:10.1021/jm030540h

Cited by 19 publications

(15 citation statements)

References 7 publications

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“…Successful disruption of the herpesvirus protease dimer offers the potential to resurrect a promising family of drug targets that were deemed undruggable due to the limited efficacy of active-site directed inhibitors. 18–20 …”

Section: Introductionmentioning

confidence: 99%

Enzyme Inhibition by Allosteric Capture of an Inactive Conformation

Lee

Shahian

Baharuddin

et al. 2011

Journal of Molecular Biology

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All members of the human herpesvirus protease family are active as weakly associating dimers, but inactive as monomers. A small molecule allosteric inhibitor of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) traps the enzyme in an inactive monomeric state where the C-terminal helices are unfolded and the hydrophobic dimer interface is exposed. NMR titration studies demonstrate that the inhibitor binds to KSHV Pr monomers with low μM affinity. A 2.0 Å resolution X-ray crystal structure of a C-terminal truncated KSHV Pr-inhibitor complex locates the binding pocket at the dimer interface and displays significant conformational perturbations at the active site, 15 Å from the allosteric site. NMR and CD data suggest that the small molecule inhibits human cytomegalovirus protease (HCMV Pr) via a similar mechanism. As all HHV proteases are functionally and structurally homologous, the inhibitor represents a class of compounds that may be developed into broad-spectrum therapeutics which allosterically regulate enzymatic activity by disrupting protein-protein interactions.

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Section: Introductionmentioning

confidence: 99%

Enzyme Inhibition by Allosteric Capture of an Inactive Conformation

Lee

Shahian

Baharuddin

et al. 2011

Journal of Molecular Biology

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“…The standard course of treatment for common herpesviral infections, a class of broad-acting viral DNA replication inhibitors such as ganciclovir and foscarnet, though widely used, exhibit undesirable toxicity, poor oral bioavailability, and in some cases inadequate efficacy8. With the incidents of drug resistance also on the rise and no other specific antivirals available, there is a need for the identification of new human herpesvirus (HHV) therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

“…Efforts by pharmaceutical companies to specifically target the active site of human cytomegalovirus protease with small molecule inhibitors has lead to either covalent inhibitors or molecules with non-ideal pharmacological properties8,14-18. In light of evidence supporting a strong linkage between the dimer interface and the protease active site, we have focused our efforts on the dimer interface for identifying novel allosteric inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of a viral enzyme by a small-molecule dimer disruptor

et al. 2009

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Small molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi’s sarcoma-associated herpesvirus (KSHV) were identified by screening an α-helical mimetic library. Subsequently, a second generation of low micromolar inhibitors with improved potency and solubility was synthesized. Complementary methods including size exclusion chromatography and 1H-13C HSQC titration using selectively labeled 13C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. 1H-15N-HSQC titration studies mapped the inhibitor binding-site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small molecule inhibitors.

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“…Initial attempts to inhibit herpesvirus proteases targeted the active site of the enzyme, relying heavily on chemical structures for covalent inhibition and/or peptidomimetic scaffolds. Specifically targeting the active site of herpesvirus proteases have not yet result in pharmacologically viable lead compounds despite some in vitro success [ 124 , 125 , 126 ]. Craik’s group reported on a small molecule, DD2 (a benzyl-substituted 4-(pyridine-2-amido) benzoic acid), able to disrupt dimerization of KSHV protease by trapping an inactive monomeric conformation [ 127 , 128 ].…”

Section: Inhibitors Of Kshv Lytic Replication Under Investigationmentioning

confidence: 99%

KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

Coen

Duraffour

Snoeck

et al. 2014

Viruses

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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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Design and Syntheses of 1,6-Naphthalene Derivatives as Selective HCMV Protease Inhibitors

Cited by 19 publications

References 7 publications

Enzyme Inhibition by Allosteric Capture of an Inactive Conformation

Enzyme Inhibition by Allosteric Capture of an Inactive Conformation

Inhibition of a viral enzyme by a small-molecule dimer disruptor

KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

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