Sunday, January 25, 2009

Diverse use of Nucleic acids.....

There is much interest in the medical uses of nucleic acids. For example, antisense, ribozymes, aptamer and RNA interference (RNAi) technologies are all being developed for potential therapeutic applications. The design of nucleic acids, particularly oligonucleotides, for in vivo delivery requires consideration of various factors including binding strength, target specificity, serum stability, resistance to nucleases and cellular uptake. A number of approaches have been proposed in order to produce oligonucleotides that have characteristics suitable for in vivo use, such as modified backbone chemistry, formulation in delivery vehicles and conjugation to various other moieties. Therapeutic oligonucleotides with characteristics suitable for systemic delivery would be particularly beneficial.

There are many oligonucleotides with modified chemical backbones, like peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methylphosphonates, phosphoramidates and thiophosphoramidates. Each of these types of oligonucleotides has reported advantages and disadvantages. For example, peptide nucleic acids (PNAs) display good nuclease resistance and binding strength, but have reduced cellular uptake in test cultures; phosphorothioates display good nuclease resistance and solubility, but are typically synthesized as P-chiral mixtures and display several sequence- non-specific biological effects; methylphosphonates display good nuclease resistance and cellular uptake, but are also typically synthesized as P-chiral mixtures and have reduced duplex stability.

The N3'-P5'phosphoramidate internucleoside linkages are reported to display favorable binding properties, nuclease resistance, and solubility (I did work for quite some time in this field and I had opportunity to interact with Dr. Sergei Gryaznov and group). Though this field is getting wider and wider with many companies trying with some innovative ideas, the real concern in this field is that the polyanionic nature of oligonucleotides reduces the ability of the compound to cross lipid membranes, limiting the efficiency of cellular uptake.But thanks to many other groups they are trying to concentrating on this issue and hope there will be may drugs in the days to come. There are many drugs already in the market by ISIS and Geron corporation has many patents to its credit in the many patents for its novel work (Dr.Sergei, Dr.Cristzina Pongracz and many others have lot of work in this field) N3'-P5'phosphoramidate internucleoside linkages. Though there were a few players in this field of nucleic acids(5-6 years' back), now a days when ever I read any medicinal chemistry news, I do find lot many companies contributing to this field of nucleic acids. Hope there will be many drugs from this field with reduced side effects....

Insulin from plants ?

With the increasing diabetic patients the requirement of insulin is also increasing. As we are aware that most insulin products are produced by bacteria in a fermenter, this is an expensive process. Now thanks to Sembiosys a Canadian company, for its novel discovery that is "when human insulin genes were inserted into Safflowers plants, the plants produced a compound called pro-insulin." Enzymes then converted this into a type of insulin called SBS-1000. Something interesting , because this SBS-1000 is identical to human insulin (Sembiosys compared its effects with insulin from other sources in healthy volunteers). Hope further studies will substantiate the conclusion and there by help to produce insulin at a cheaper rate . More.....

Use of Liquid crystals in high-resolution digital X-rays !

We have seen many applications of liquid crystals, but now something interesting like "X-ray light valve" (a term coined by Dr.John Rowlands). This finds importance because the use of liquid crystals reduces the cost of high-resolution digital X-rays by many folds. As the use of digital X rays is becoming essential (because its simple to analyse, manipulate and store-in comparison with the presently used ones). Most of them work by using a layer of amorphous selenium to convert the X-rays into electric charge. This charge image is then recorded using an array of transistors and other electronic components, akin to those used in some digital cameras.

X-rays cannot be easily focused, so X-ray machines work by recording the shadow of an object rather than a focused image. That means the recording medium, be it an electronic imager or conventional X-ray film, must be at least the same size as the object being scanned and this add to the cost of digitally imaging. Thanks to Dr.Rowland and his group for X-ray light valve-consisting of a layer of liquid crystal - which is opaque or transparent depending on whether an electric charge is present - covered with a layer of amorphous selenium. These layers are sandwiched between a pair of electrodes which generate an electric field across them. When an X-ray is taken, the rays that hit the selenium layer generate a charge which is drawn towards the liquid crystal by the electric field. This makes the liquid crystal transparent at those locations. The overall pattern of transparency and opacity can be read off the liquid crystal layer using a light-based digital scanner and presented as a digital image. This research is of significance because of the fact that it separates the read-out system from the X-ray mechanism.

As pulmonary tuberculosis is becoming an epidemic in the developing countries, development of this technique is a boon to the people.

When I was working for my Ph.D., my guide (Dr. Shankar C. Bennur  (now retired) Professor of Organic Chemistry, Karnatak University Dharwad, Karnatak, India) used to tell me that the liquid crystals will have many fold uses in the days to come. He did work (UFSC, Florianopolis, SC, Brazil) on the synthesis of many liquid crystals and used to tell me about his experience with this interesting field (which was at nascent stage). Whenever we used to get products (in my case, the compounds had methylene aminoxy methyl moiety) with low melting points, he  used to elaborate about  smectic point./long chain compounds.....Hope,  he will be happy about this innovative idea. Congrats Dr.Rowland......

Ref :

Sunday, January 18, 2009

An abondoned anticancer drug's rebirth...

α-Difluoromethylornithine or DFMO, which was developed as a cancer therapy and later shelved because of toxicity concerns, has been around since the 1970s. But over the past five years, it has undergone a rebirth as a chemoprevention agent, first showing efficacy in animal models of human cancer and more recently in human prostate and colon cancer. A recent study shows that it likely works in a large cast of tumors, even those having poor prognosis, like high-risk neuroblastoma (a childhood malignancy of the sympathetic nervous system, that accounts for accounts for nearly eight percent of all childhood cancers and 15 percent of pediatric cancer-related deaths. Its solid tumors arise from developing nerve cells, most commonly in the adrenal gland, but also in the abdomen, neck, and chest. Neuroblastoma usually occurs in infants and young children, appearing twice as frequently during the first year of life than in the second.

The best-known genetic alteration involved in neuroblastoma is the amplification of the proto-oncogene—a molecule that when overexpressed can cause cancer—called MYCN. Amplification of MYCN occurs in about 20 percent of all neuroblastoma and is associated with the high-risk form of the disease. Targeting this and related genes directly might be therapeutically tempting, the study noted, but highly problematic because the oncoproteins they produce are also required for the growth of most normal cell types. And that is why Dr. John Cleveland and colleagues focused on inhibiting ornithine decarboxylase (Odc), a protein that contributes to cancer cell growth and that is a target of the proto-oncogene MYCN. Increased levels of Odc are common in cancer, and forced Odc expression in animal models has been shown to lead to increased tumor incidence. Recent findings have shown that Odc overexpression is also an indication of poor prognosis in neuroblastoma. DFMO, the drug used by the Cleveland team, inhibits the activity of Odc. One mor interesting is at lower dose the drug is specific and it has impact on Odc only. Though the toxicity ealrier reported has to be still ascertained, it may be time to revisit the issue as the study showed that transient treatment with DFMO is sufficient to provide chemoprevention and may show benefit for this otherwise lethal malignancy. Hope the detailed study will have something inthe near future....

Structure of key Ebola protein solved.....

The Ebola virus can cause hemorrhagic fever that is usually fatal. According to the Center for Disease Control and Prevention, outbreaks have caused more than 1,000 deaths, mostly in Central Africa, since it was first recognized in 1976. Approved treatments for these infections are currently lacking. The Ebola VP35 protein is multifunctional, acting as a component of the viral RNA polymerase complex, a viral assembly factor, and an inhibitor of host interferon (IFN) production. Mutation of select basic residues within the C-terminal half of VP35 abrogates its dsRNA-binding activity, impairs VP35-mediated IFN antagonism, and attenuates EBOV growth in vitro and in vivo. Because VP35 contributes to viral escape from host innate immunity and is required for EBOV virulence, understanding the structural basis for VP35 dsRNA binding, which correlates with suppression of IFN activity, is of high importance.

A team led by Gaya Amarasinghe, an assistant professor in biochemistry, biophysics and molecular biology, has recently solved the structure from a key part of the Ebola protein known as VP35. This protien interferes with the natural resistance of host cells against viral infections. when viruses infect cells, the host immune system can fight to eventually clear the virus. But with Ebola infections, the ability of the host to mount a defense against the invading virus is lost
I think this if not controlled will be like deadly epidemic AIDS (and even worst than this...), because of the fact that the VP35 protein interferes with the host's innate immune pathways that form the first line of defense against pathogens. With the advent of technologies like combination of X-ray crystallography and nucleic magnetic resonance spectroscopy the team has achieved the structure by using non-infectious protein samples. Hope this template (known structure) will help the drug discoverers to identify and design drugs that potentially bind with VP35 and their by substantiate anti-viral drug discovery. Congrats to Gaya Amarashinghe and his team. More ....

Saturday, January 17, 2009

Genetic modification of E. coli, a bacterium to produce long-chain alcohols essential in the creation of biofuels- a new avenue of biofules ?

Alcohols were never synthesized beyond five carbons. Now, James Liao, UCLA professor of chemical and biomolecular engineering and his team have figured out a way to engineer proteins for a whole new pathway in E. coli to produce longer-chain alcohols with up to eight carbon atoms. This research is of interesting because of the fact that, longer-chain alcohols with five or more carbon atoms, pack more energy into a smaller space and are easier to separate from water. Thus making them less volatile and corrosive than the commercially available biofuel ethanol. The greater the number of carbon atoms, the higher the density of the biofuel.

Encouraged by the fact that organisms typically produce a large number of amino acids, which are the building blocks of proteins. In their research, Liao's team examined the metabolism of amino acids in E. coli and changed the metabolic pathway of the bacterium by inserting two specially coded genes. One gene, from a cheese-making bacterium, and another, from a type of yeast often used in baking and brewing, were altered to enable E. coli's amino acid precursor, keto acid, to continue the chain-elongation process that ultimately resulted in longer-chain alcohols.

Though this new frontier of biofuels production from organisms has the potential to address significant issues in global warming, the scientific significance of successful genetic modification could also mean great benefits beyond the environment. Hope this reaerch will go a longway in finding solution to the alternative ways for biofuels and also may have its impact in the fields of Polymer science and Drug manufacturing . More....

Wednesday, January 14, 2009

A new avenue for TB therapy !

TB bacteria actually sends signals that encourage the growth of those organized granuloma structures, and for good reason: each granuloma serves as a kind of hub for the infectious bugs in the early stages of infection, allowing them to expand further and spread throughout the body. Which is something interesting in he sense that the earlier believed fact (i.e., masses of immune cells that form as a hallmark of tuberculosis (TB) have long been thought to be the body's way of trying to protect itself by literally walling off the bacteria) is being ruled out?. Scientists thought they were protective, but they are not - at least not in early infection. The bacteria use them to reproduce and disseminate themselves.
Not only do the bacteria expand themselves within the first granuloma to form, she added, but some of the immune cells in that initial mass leave to start new granulomas elsewhere. Those new granulomas then also serve as breeding grounds for the bacteria. The finding (Lalita Ramakrishnan and J.Davis). suggests a new avenue for TB therapy at an important time in the struggle against TB infection (not only the increasing number of patients, AIDS with TB and drug resistant TB). So if one can prevent granulomas that might be therapeutic either by intercepting the bacterial signal that spurs granulomas' formation or by manipulating the human immune system in some other way. Hope this research will go a long way in finding the solution to the epidemic drug resistant TB........

Blood type - a new weapon in battle against HIV infection ?

A carbohydrate-containing antigen, termed Pk blood group which is distinct from the well-known ABO and Rh blood grouping systems, is present at variable levels on the surface of white and red blood cells in the general population. Though the percent of this type of blood Pk, is less (1 in million). The interesting thing is that, those produce excess of this blood group antigen have dramatically reduced sensitivity to HIV infection. Conversely, another slightly more common subgroup of people who do not produce any Pk (5 in a million) was found to be much more susceptible to the virus.

Though the study does not suggest that blood type alone will not determine one will get HIV exclusivel. As per the research work by Dr. Don Branch of Canadian Blood Services, it does suggest that individuals who are exposed to the virus, may be helped or hindered by their blood status in fighting the infection. The study is substantiated by the fact that by increasing the level of the Pk antigen in cells in the laboratory also resulted in heightened resistance to HIV, while lowering it increased susceptibility.

The Pk molecule has been previously studied extensively by The Research Institute at the Hospital for Sick Children Senior Scientist Dr. Cliff Lingwood; Lund University's Dr. Martin Olsson has identified underlying genetic reasons for Pk blood group variation. Hope this conclusion may pave the way for novel therapeutic approaches to induce HIV resistance and promote further understanding of the pandemic as a whole," says Dr. Lingwood.

Sunday, January 11, 2009

Clioquinol as anti-aging agent?

Clioquinol (5-Chloro-7-iodo-8-hydroxyquinoline), an 80-year old drug once used to treat diarrhea and other gastrointestinal disorders - can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases, something interesting and a serendipity again to the kitty of so many drugs...And the authors claims that Clioquinol is a very powerful inhibitor of clock-1, because clock-1 affects longevity in invertebrates and mice and hence can be used to treat the three age-dependent neurodegenerative diseases. Though detailed investigation is essential and one need to explain why, the drug was withdrawn from the market after being blamed for a devastating outbreak of subacute myelo-optic neuropathy (SMON) in Japan in the 1960s. Hope some solid conclusion will be arrived in the near future..


Olanzapine as long-acting injection (LAI) for acute and maintenance treatment of schizophrenia.?

Olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) is one of the most commonly used drugs for atypical antipsychotics. Olanzapine has been approved by the FDA for the treatment of schizophrenia, acute mania in bipolar disorder, agitation associated with schizophrenia and bipolar disorder, and as maintenance treatment in bipolar disorder and psychotic depression. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.

Olanzapine's antipsychotic activity is mediated primarily by antagonism (blocking or inhibition) at dopamine receptors.

FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics.

Lilly is continuing to work with the agency on the new drug application (NDA). I think Lilly, has a come with a smart move like NDA, becoz., the FDA does not require any additional clinical trials for the continued review of the NDA. Per the agency's request, Lilly is preparing a proposed Risk Evaluation and Mitigation Strategy (REMS), which will be submitted in the near future. Hope this drug will not have the said side effects. A ray of hope for schizophrenia patients ? time will tell the story, best of luck Lilly....

New Benzothiazepine test to catch sports cheats ?

Though there are many tests for drugs (performance enhancers) for the sportpersons, they will try to use the drugs (wherein there are no tests to prove them guilty). Thanks to German research team who have come up with a new test. I am sure this test will try to combat the 'emerging drugs' and bring a sactity to the sport world.

The test detects a core chemical structure belonging to a class of compounds called benzothiazepines. These compounds stabilise protein channels that would otherwise "leak" calcium from muscle cells during strenuous exercise. Calcium is needed for muscle contraction and this "leaking" effect weakens the contractions and is a causal factor in muscle fatigue.

JTV-519 and S-107, benzothiazepines currently in development for the treatment of heart abnormalities, are known to increase endurance in mice. Although they have not yet entered human clinical trials, both can be detected using the test.

As soon as these drugs enter human clinical trials, there is a huge potential for them to be m isused in sports. This preventive research lets us prepare before these compounds are officially launched, says Mario Thevis, (lot of work done by his group in the spectroscopy field) Director of the Center for Preventive Doping Research at the German Sport University of Cologne, Germany, who led the research. The advantage of high resolution mass spectrometry, JTV-519 and S-107 can be detected in spiked urine at concentrations as low as 0.1 nanograms/ml. And hope they will try to achieve the detailed study of the metabolites also, which will further substantaite the evidence...More...

Thursday, January 8, 2009

Mechanism of synthesizing estrogen visualized.....

Dr. Ghosh lab, has determined the structures of all three of the enzymes (aromatase, sulfatase and 17beta-hydroxysteroid dehydrogenase type 1) involved in controlling estrogen levels that can serve as drug targets for estrogen-dependent tumors in breast cancer. It s really interesting now as the structures of all three key enzymes implicated in estrogen-dependant breast cancers are known, one can have the drugs those can target these three enzymes. Hope with the help of molecular modelling, the goal to have a personalized cocktail of inhibitors customized to the specific treatment needs of each patient can be achieved in the days to come. Hats off to Dr.Ghosh and co workers and wish them to achieve the next target i.e., chemical mechanism involved in the conversion of androgens to estrogens. Once they achieve the next target, hope we will have more Aromatase inhibitor drugs with reduced side effects.....

Thursday, January 1, 2009

Happy new Year 2009

Wish you all, A happy, prosperous and peaceful New Year-2009.