In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Bordier, Bruno B.; Ohkanda, Junko; Liu, Ping; Lee, So‐Young; Salazar, F.H.; Marion, Patricia L.; Ohashi, Kazuhiko; Meuse, Leonard; Kay, Mark A.; Casey, John L.; Sebti, Saı̈d M.; Hamilton, Andrew D.; Glenn, Jeffrey S.

doi:10.1172/jci200317704

Cited by 38 publications

(40 citation statements)

References 32 publications

(26 reference statements)

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“…A better comprehension of this mechanism could lead to significant progress in the development of more specific FTase inhibitors, with increased activity for cancer treatment, with potential value in the treatment of parasitic infections, or even with application as antiviral agents. 37 In this study we have analyzed a key paradox known as ''the product coordination ambiguity,'' 36 which arises from the existence of contradicting experimental evidence, both in favor and against farnesylated thioether product coordination to the active site Zn coordination sphere (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Theoretical studies on farnesyl transferase: Evidence for thioether product coordination to the active‐site zinc sphere

2007

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Farnesyltransferase (FTase), an interesting zinc metaloenzyme, has been the subject of great attention in anticancer research over the last decade. However, despite the major accomplishments in the field, some very pungent questions on the farnesylation mechanism still persist. In this study, the authors have analyzed a mechanistic paradox that arises from the existence of several contradicting and inconclusive experimental evidence regarding the existence of direct coordination between the active-site zinc cation and the thioether from the farnesylated peptide product, which include UV-vis spectroscopy data on a Co(2+)-substituted FTase, two X-ray crystallographic structures of the FTase-product complex, and extended X-ray absorption fine structure results. Using high-level theoretical calculations on two models of different sizes, and QM/MM calculations on the full enzyme, the authors have shown that the farnesylated product is Zn coordinated, and that a subsequent step where this Zn bond is broken is coherent with the available kinetic results. Furthermore, an explanation for the contradicting experimental evidence is suggested.

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Section: Introductionmentioning

confidence: 99%

Theoretical studies on farnesyl transferase: Evidence for thioether product coordination to the active‐site zinc sphere

2007

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“…This step involves the attachment of a 15‐carbon prenyl group, farnesyl, to the large delta antigen, a reaction catalyzed by farnesyl transferase . Prenylation inhibitors have been shown to specifically abolish HDV‐like particle production in vitro and in vivo . Recently, the first human data have been reported .…”

mentioning

confidence: 99%

Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV‐1 study

Yurdaydın¹,

Keskın²,

Kalkan³

et al. 2018

Hepatology

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123

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The cytochrome P450 3A4 inhibitor, RTV, allows a lower LNF dose to be used while achieving higher levels of postabsorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG-IFNα achieved more substantial and rapid HDV-RNA reduction, compared to historical responses with PEG-IFNα alone. Twelve weeks of LNF can result in posttreatment HDV-RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. (Hepatology 2018;67:1224-1236).

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“…As a consequence, preventing prenylation abolishes virus particle formation. This approach has been initially evaluated in vitro [49] and more recently in vivo in a novel mouse model that supports HDV replication [50]. Using this model, a prenylation inhibitor was shown to determine HDV clearance, thus opening the perspective of a clinical evaluation of this novel class of HDV inhibitors in chronic hepatitis D. However, until novel classes of antiviral agents capable of interfering with the life cycle of this unique virus become available, treatment of chronic hepatitis D will remain a major challenge for both clinicians and virologists.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Treatment of chronic hepatitis D

Farci

Chessa

Balestrieri

et al. 2007

Journal of Viral Hepatitis

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Despite recent advances in the treatment of chronic viral hepatitis, therapy of chronic hepatitis D is not yet satisfactory. The only option currently available is interferon-alpha (IFN), whose efficacy is related to the dose and duration of treatment. However, the rate of sustained hepatitis D virus (HDV) clearance after a 1-year course with high doses of standard IFN is low. Better results have recently been reported with pegylated IFN both in IFN-naïve and in previous nonresponders to standard IFN, suggesting the use of pegylated IFN as a first-line therapy in chronic hepatitis D. Nucleoside analogues that inhibit hepatitis B virus (HBV) are ineffective against HDV and combination therapy with lamivudine or ribavirin has not shown significant advantages over monotherapy with either standard or pegylated IFN. Because the ultimate goal of treatment is eradication of both HDV and HBV, in responders IFN therapy should be continued as long as possible until the loss of hepatitis B surface antigen, adjusting the dose to patient tolerance. However, because side-effects are common, continuous monitoring is mandatory. Although the first results obtained with pegylated IFN have been encouraging, the rate of sustained virological response is still low and the rate of relapse high, emphasizing the need for developing novel classes of antivirals specifically interfering with the life cycle of this unique virus.

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In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Cited by 38 publications

References 32 publications

Theoretical studies on farnesyl transferase: Evidence for thioether product coordination to the active‐site zinc sphere

Theoretical studies on farnesyl transferase: Evidence for thioether product coordination to the active‐site zinc sphere

Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV‐1 study

Treatment of chronic hepatitis D

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