这就是那个德国的药HAP

moonshadow

Date: Sun, 09 Feb 2003 22:48:08 -0800
Subject: [hepcan] INFO: Inhibition of HBV replication by drug-induced depletion
of nucleocapsids


SourceURL:http://www.gastrohep.com/news/news.asp?id=1839

Inhibition of HBV replication by drug-induced depletion of nucleocapsids

Heteroaryldihydropyrimidines, for the treatment of HBV infection, inhibit
capsid formation, find researchers in the latest issue of Science.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease.

However, at this stage only interferon-alpha and the nucleosidic inhibitors
of the viral polymerase, 3TC and adefovir, are approved for therapy.

These therapies are limited by the side effects of interferon, and by the
substantial resistance of the virus to nucleosidic inhibitors.

Heteroaryldihydropyrimidines prevent the proper formation of viral core
particles.
Science

Therefore, potent new antiviral compounds suitable for monotherapy or
combination therapy are highly desired.

In this study, researchers from Germany explored the drug profile and
mechanisms of 2 compounds (Bay 38-7690 and Bay 39-5493), known as
heteroaryldihydropyrimidines (HAP).

HAP prevents the proper formation of viral core particles (nucleocapsids),
which are the site of viral DNA replication.

The team determined that Bay 38-7690 treatment interfered with the
formation of core particles, without affecting core protein levels.

In addition, the team investigated binding between tritium-labeled Bay
39-5493 and HBV core particles. Binding was found to be specific for the
human virus, enantio-selective and reversible.

Dr Karl Deres's team concluded, "We present a substance class for the
treatment of HBV infection that displays a highly specific antiviral
principle, namely, inhibition of capsid formation, concomitant with a
reduced half-life of the core protein."

"The clinical efficacy of this treatment modality of HBV infection will now
need to be demonstrated".

Science 2003; 299(5608): 893-6.
10 February 2003

清照

Activity of New Anti-HBV Agents Elucidated

NEW YORK (Reuters Health) Feb 06 - A new class of compounds, known as
heteroaryldihydropyrimidines (HAPs), has been shown to inhibit hepatitis B
virus (HBV) replication in the laboratory and in vivo. Now, new study
findings suggest that this anti-HBV activity is due to inhibition of
nucleocapsid formation.

Currently, interferon-alpha and nucleosidic inhibitors of HBV polymerase are
the only drugs approved for the treatment of chronic HBV infection, lead
author Dr. Karl Deres, from Bayer Research Center in Wupertal, Germany, and
colleagues note.

However, interferon-alpha is associated with dose-limiting side effects and
HBV strains often develop resistance to the polymerase inhibitors.
Therefore, new anti-HBV agents with different mechanisms of action are
needed, the researchers note.

Unlike other agents, HAPs are non-nucleosidic and do not inhibit the HBV
polymerase, the investigators note. Although they have been shown to be
highly potent inhibitors of HBV replication, their exact mechanism of action
has been unclear.

In a study reported in the February 7th issue of Science, Dr. Deres' team
analyzed the activity of these drugs in cell culture. The researchers found
that the HAPs work by inhibiting formation of the nucleocapsids needed for
viral replication. This was associated with a reduction in core protein
levels.

Of the various HAPs tested, one (Bay 41-4109) has shown particular promise
as a potential therapeutic agent. "It has a demonstrated efficacy in HBV
transgenic mice and a suitable preclinical pharmacokinetic and toxicology
profile," the authors note. "The clinical efficacy of this treatment...will
now need to be demonstrated."

Science 2003;299:893-896.

清照

异芳基二氧嘧啶 (heteroaryldihydropyrimidines HAPs)是一类新的化合物，具有抑制HBV病毒复制的效果，而与其他几类抗病毒药物的作用机理完全不同。

与核苷类药物不同，HAPs没有抑制HBV的DNA聚合酶，目前研究人员还没有查明HAPs抑制病毒复制的具体机制。由于这类药物对病毒聚合酶没有作用，因此推测它可能不会出现耐药的病毒变异。

2003年2 月发表在Science 上的一项研究表明，它是通过抑制病毒核蛋白外壳的形成，来抑制病毒复制的，与HBV核心蛋白水平减少相关。而核蛋白壳是病毒复制所需装配的病毒颗粒。

在所有测试过的HAPs化合物中， Bay 41 4109 是最有潜力的，已经证明它在HBV转基因小鼠的治疗中有效，并且潜在的药物不良反应和毒性也较为合适（可以耐受）。目前尚未在人体中测试，还需要进一步的临床试验来证明它的效果。