Editorial: In vitro mechanistic evaluation of nucleic acid polymers: A cautionary tale

Vaillant, Andrew

doi:10.1016/j.omtn.2022.03.002

Cited by 11 publications

(11 citation statements)

References 35 publications

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“…Another way to improve inhibition of the mature nucleocapsid formation and subsequent virosuppression could come from the R&D of drugs targeting HBV nucleocapsid assembly; these drugs are mainly called "core assembly modulators" (CpAMs) (Viswanathan et al, 2020). CpAMs act "upstream" of NAs (in the pathway of mature nucleocapsid formation) by preventing the incorporation of pgRNA into capsid and therefore its subsequent conversion into rcDNA by HBV polymerase; the latter being exclusively active within an already formed capsid (Fig.…”

Section: Strategies To Improve the Inhibition Of Mature Hbv Nucleocap...mentioning

confidence: 99%

“…2) (Seeger et al, 2015;Tsukuda and Watashi, 2020). Many CpAMs, belonging to two main classes in terms of mode of action (Class-Em or Class-Ab) have been identified and some of them evaluated in clinical trials (Yardeni et al, 2023;Viswanathan et al, 2020). The first and second generation of CpAMs (e.g.…”

Section: Strategies To Improve the Inhibition Of Mature Hbv Nucleocap...mentioning

confidence: 99%

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Therapies against chronic hepatitis B infections: The times they are a-changin’, but the changing is slow!

Durantel

2023

Antiviral Research

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Section: Strategies To Improve the Inhibition Of Mature Hbv Nucleocap...mentioning

confidence: 99%

Section: Strategies To Improve the Inhibition Of Mature Hbv Nucleocap...mentioning

confidence: 99%

Therapies against chronic hepatitis B infections: The times they are a-changin’, but the changing is slow!

Durantel

2023

Antiviral Research

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“…Recently, the HSP40 chaperone DNAJB12 was shown to be required for SVP assembly and secretion and selectively targeted by NAPs [18]. Recently, the development of LNA-modified NAPs (STOPs) was attempted, but these compounds ultimately had no effect in human studies [94], primarily due to the fact that the structural rigidity imparted by LNA modification destroys NAP functionality [95]. Unfortunately, the in vitro analyses of these compounds used to support clinical studies [96] were highly flawed and shown to be artifactual [95].…”

Section: Nap Effects In Vitro In Vivo and Humans In Hbv Infectionmentioning

confidence: 99%

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

Vaillant¹

2022

Viruses

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Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection.

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“…The mechanism of action of NAPs in HBV infection relies on its interaction with host protein DNAJB12 within the Endoplasmic Reticulum – Golgi intermediate compartment (ERGIC). It is postulated that NAPs inhibit DNAJB12 (DnaJ homologue subfamily B member 12) that is required for the formation of HBV subviral particles within the ERGIC 78–80 . Currently, two candidate drugs – REP 2139 and REP 2165 – showed promising results in mediating HDV RNA clearance and HBV functional cure in clinical trials.…”

Section: Novel Treatmentsmentioning

confidence: 99%

Future anti‐HDV treatment strategies, including those aimed at HBV functional cure

Tan

Lee

Huang

et al. 2022

Liver International

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HDV is a defective virus that uses the HBV surface antigen to enter hepatocytes. It is associated with an accelerated course of liver fibrosis progression and an increased risk of hepatocellular carcinoma. Negative HDV RNA 24 weeks after the end of therapy has been proposed as an endpoint but late relapses make this endpoint suboptimal, hence HBsAg loss appears to be more appropriate. Current HBV antiviral agents have poor activity against HDV hence the search for improved therapy. Drugs only active against HDV, such as lonafarnib, have shown efficacy in combination with nucleoside analogues and peginterferon, but do not lead to HBsAg loss. HBsAg loss sustained 24 weeks after the end of therapy with negative HBV DNA is termed functional cure.

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Editorial: In vitro mechanistic evaluation of nucleic acid polymers: A cautionary tale

Cited by 11 publications

References 35 publications

Therapies against chronic hepatitis B infections: The times they are a-changin’, but the changing is slow!

Therapies against chronic hepatitis B infections: The times they are a-changin’, but the changing is slow!

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

Future anti‐HDV treatment strategies, including those aimed at HBV functional cure

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