4.1.4 Other Direct-Acting Antivirals
NS3 helicase is an enzyme that binds to double-stranded HCV RNA and unwinds it so the resulting strands can be used to produce more RNA or translate it into proteins. If these strands couldn’t unwind, HCV could not reproduce. The helicase is Y-shaped, with 3 linked areas separated by clefts, which are possible targets for drugs. The newer HCV helicase inhibitors contain thiodiazonium compounds. So far, there has not been much success in viral reduction.
A technique to track the unwinding process, developed at the University of Illinois, crystallizes the proteins, and tags each molecule with a fluorescent label on each strand of its double-stranded region. The growing distance between the strands can then be followed as they unwind, and the speed of the process can be measured. The scientists found that the DNA unwinds in “jumps”, since the pairs of nucleotides must unhitch themselves before unwinding.
"It's like you're adding tension to a spring," said Taekjip Ha, a professor at the U. of Illinois. "You are loading the spring with small
mechanical movements until finally you have accumulated enough tension on the DNA-protein complex to cause the rapid unwinding of three base
pairs." Each process of unwinding takes the input of 3 adenosine triphosphate (ATP) molecules, a cellular source of fuel.
Vertex Pharmaceuticals is in the preclinical stage of developing an HCV NS3 helicase inhibitor. Vertex has identified the three-dimensional structure of NS3 helicase, and is studying how it works. Hopefully this knowledge will help design potent inhibitors of this enzyme ( www.vpharm.com ).
Vertex’s helicase inhibitor is thiodiazonium-based. (Curr. Med. Chem. - Anti-Infective Agents, 2002, 1, 163-176) There is nothing about this drug on Vertex’s pipeline since 2004.
Genelabs Technologies, Inc. On April 20, 2000, Genelabs announced its discovery of a new class of antiviral compounds, which
have demonstrated effectiveness against HCV, as well as other flaviviruses. Some of these compounds are helicase inhibitors. Genelabs is
currently conducting in vivo studies to evaluate the antiviral effect in animals as well as evaluating the in vitro antiviral effect on other
QU663 is a new nucleotide-mimicking inhibitor under investigation. “...a potent new selective inhibitor of the helicase reaction of HCV NS3 (K(i) = 0.75 microM), competing with the nucleic acid substrate without affecting ATPase function, even at high concentrations.” (Maga G, et al Biochemistry. 2005 Jul 19;44(28):9637-44.)
Researchers Peter Borowski and colleagues have studied an agent called Tropolone (2-hydroxy-2,4,6-heptatriene-1-one) as an HCV NS3 helicase inhibitor.
The results were not expected, showing that the agent and its derivatives don’t “unwind” the virus, nor do they block the NTP-binding site.
They occupy an allosteric regulatory site.
(http://lib.bioinfo.pl/pmid:17542155 Antivir Chem Chemother. 2007;18 (2):103-9 17542155)
The internal ribosome initiation site (IRES) is a part of the hepatitis C virus that is found in different genotypes. It is an essential part of the replication process, so scientists believe that, by finding an IRES inhibitor, there will be a decreased production of the virus. Several companies are working with possible IRES inhibitors. It has recently been discovered that interferons work because they are IRES inhibitors. (Liver Int, 2005; 25(3):580-594)
VGX Pharmaceuticals announced the commencement of Phase II trials of their IRES inhibitor Mifepristone (VGX-410) with 48 HCV+ patients in November of 2005 to assess the anti-HCV activity of the drug. The patients were to receive 3 dose levels orally, during 28 days.
The trial will assess the effects on the immune system before and during treatment. Completion was expected in November 2007. The drug has
already been proven safe, since a similar formulation if the drug was approved by the US FDA for medical abortion, and for several malignant and
non-malignant conditions, for one year. Going by the cell culture tests, the company expects viral clearance in 50-90%.
(http://clinicaltrials.gov Nov 15, 2005)
MERCK is using artificial ribozymes to target HCV IRES in vitro and in vivo (Curr Opin Mol Ther. 2001 Jun;3(3):278-87).
Merck has partnered with PTC Therapeutics to research and develop these therapies.
(www.schering-plough.com Mar 2006)
RNAi (RNA interference) is a mechanism used by the body’s cells to control the expression of genes and the replication of viruses with the
help of small interfering RNA molecules. RNAi is the newest nucleic-acid based therapy being studied for HCV infection. All regions of the virus
are susceptible to RNAi. There are 2 types of RNA viruses - those with a "sense" strand of RNA, like HCV, and those with an "antisense" strand
(with the opposite coded genetic information). Antisense therapy involves using "therapeutic" strands of RNA which make it difficult if not
impossible for the viral RNA to perform its function. Antisense targets parts of the HCV genetic code that probably don’t mutate over time, and
attacks the microRNA required for HCV to multiply.
“Antisense drugs are short, chemically-modified RNA-like and DNA-like molecules that scientists design to complement a small, specific
segment of messenger RNA, or mRNA.”
Santaris Pharma announced Phase IIa data for Miravirsen (formerly SPC3649) monotherapy which showed a 2-3 log drop in HCV with only 4 weeks of treatment. The virus was undetectable in 4 of the 9 patients treated with the highest dose. The viral drop has been maintained for over 4 weeks after ending treatment. Miravirsen is a microRNA-targeted drug. It inhibits miR-122 which the virus needs to accumulate. It can be safely used alone or combined with direct acting antivirals, providing an IFN-free treatment for multiple genotypes.
The drug was given as 5 subcutaneous injections, one per week. It was well tolerated by the patients. MicroRNAs are a kind of master
regulator of gene expression, not only in hepatitis C, but in other diseases, as well. They are single molecules, and are possible targets for
drugs to control many diseases. The company uses a Locked Nucleic Acid (LNA) drug platform which overcomes the limitations of antisense and
siRNA technologies and has properties that permit delivery of drugs without problematic delivery vehicles.
Before being acquired by Merck, Sirna Therapeutics presented non-human primate Hep C data and claimed treatment success in a few animals, but
because of a legal problem about the delivery system, progress has stalled. Benitec had plans for its Hep C program involving clinical trials,
but ran out of money. They have moved back to Australia, and their Hep C program has been taken over by Tacere.
(http://rnaitherapeutics.blogspot.com/20070601archive.html June 8. 2007)
Oncolys BioPharma and Tacere Therapeutics have partnered to develop TT-033, an RNA interference (RNAi) product which Oncolys will market as OBP-701. The product contains 3 different RNAi elements inside an AAV protein coat. Using AAV to penetrate liver cells has been shown to work effectively in preclinical studies in animals, without being toxic. This “cocktail in one drug” attacks HCV at 3 different sites, and is thought to be effective for all genotypes. Phase I clinical trials are expected to begin in late 2008.
(www.newsrx.com/library/newsletters/Hepatitis-Weekly/615646.html Jun 21, 2007)
ITX-5061: The company iTherx has produced ITX-5061, an HCV Entry Inhibitor, as monotherapy for viral load reductions, safety and tolerability. This drug is designed to be part of a “cocktail” of HCV inhibitors that prevent entry of HCV into the host cell. The drug has shown to be effective in previous studies by inhibiting both genotype 1 and genotype 2 HCV viruses. (hcvadvocate.org February 9, 2009 and www.itherx.com/hepatitis.html)
A Phase I trial is now in progress (2011), studying the drug in treatment-naïve patients. The company has begun recruiting about 20 patients
for a Phase Ib study in liver transplant patients. Half will not receive the drug—only supportive care—and the other half will receive ITX-5061
for 7 days. The product has also been shown to be a powerful antiviral in preclinical trials, and has a good safety profile. The researchers
believe that this product can prevent re-infection of the new liver—something that transplant patients experience universally.
DEB025 (Alisporivir) is a cyclophilin inhibitor produced by Novartis. It affects the host proteins that the virus needs to replicate. The product has been shown to be effective against all genotypes. This study treated G1 (genotype 1) treatment-naïve patients, with the product alone or combined with SOC (standard of care, or PegIFN+RBV), for 48 weeks. The main side effect was an increase in bilirubin, and was reversible. The results from week 24 post-treatment showed SVR (sustained viral response) in 76% of the patients in the arm including SOC, vs 55% for SOC alone. The drug is now being used in a Phase III study for G1 untreated patients. (EASL 2011)
Biotron produces BIT225, a drug that targets the p7 protein of HCV, which is needed “for production and release of infectious virus from infected cells.” Preclinical studies showed that BIT225 worked well combined with IFN/RBV and with the new NS5B-inhibitors.
The first stage of Phase II trials is completed. Twelve genotype 1 patients were treated with BIT225 alone.
The second stage is underway, adding an additional 12 patients for 4 more weeks, including patients outside Australia, and combining either the drug or a placebo with pegIFN/RBV.
Results were expected in June 2011, but news from the company indicated a delay.
(http://hepatitiscnewdrugs.blogspot.com/search?q=BIT225+ March 10, 2011)
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