Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-11-10
2001-07-31
Mertz, Prema (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S069100, C435S252300, C435S320100, C435S325000, C530S351000
Reexamination Certificate
active
06268157
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the invention
This invention relates to a method for screening and molecular designing pharmaceuticals useful for various diseases on bone, cartilage, liver, kidney, skin, immune system, central system and the like, or benign tumor, malignant tumor, hyperplasia, fibrosis and the like.
2. Related Background Art
It has been attempted to develop TGF-&bgr; super family molecule itself, or antagonist or agonist thereof as a pharmaceutical based on focusing the function of TGF-&bgr; super family, and some pharmaceutical screening methods therefor have been proposed.
For example, (1) as a method for screening by using cell system, there are screening methods for agonist or antagonist by using the activity of TGF-&bgr; super family in growing, differentiating, killing or maintaining animal cells as an indicator. Those methods are, for example, (i) a screening method using inhibition activity of TGF-&bgr; on the growth of a tumor cell, or propagation accelerating activity of it on the growth of another tumor cell as an indicator, (ii) a screening method focusing on the immuno suppression activity of TGF-&bgr; and (iii) a screening method focusing on production accelerating effect on extracellular matrix by TGF-&bgr;. Furthermore, (2) a screening method focusing on the interaction between TGF-&bgr; super family and TGF-&bgr; receptor super family is known.
However, it is known that TGF-&bgr; super family has significantly wide-ranging functions, and thus, a mere agonist or antagonist for TGF-&bgr; super family may have a problem such that main function and side function can not be sufficiently differentiated, and consequently they are not sufficient for a screeningmethod for pharmaceuticals. That is, the above screening method can not differentiate only main function from other functions, and very likely screen materials with low specificity not to be an candidate for pharmaceuticals. Furthermore, even if a useful candidate for pharmaceuticals could be screened, it still remains difficulty to find guideline for synthesizing a useful derivatives and to do molecular designing.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a novel method for screening pharmaceuticals, which overcomes the above prior art's problems.
As a result of intensive efforts to overcome the above-mentioned problems, the present inventor succeeded to develop a screening method for pharmaceuticals (inhibitor, accelerator etc.) with more specificity and a method for molecular designing them, based on a novel principle by focusing on intracellular signal transfer mechanism of TGF-&bgr; receptor super family, and accomplished this invention.
Although a pathway via Smad molecule and the MAP kinase pathway via TAB1, TAK1 and the like have been known as an intracellular transfer mechanism of TGF-&bgr; receptor super family, it is little understood how the expression of the targeted gene is finally controlled by these pathways. Especially, it is known that Smad molecule affects to transcription control in nucleus, but a transcription control factor interacted with Smad molecule in higher animal cell has not been determined.
The present inventor demonstrated that the interaction among Smad molecule, intranuclear receptor and transcription coupling factor is important physiologically in the transcription control mechanism of Smad molecule. Under the above-mentioned knowledge, the present inventor developed a method for screening and a method for molecular designing pharmaceuticals based on the novel principle which focuses on the transcription control mechanism via the intracellular signal transfer mechanism of TGF-&bgr; receptor super family.
In the signal transfer pathway of Smad, as a pharmacofunction being presumable from the prior art, there are (i) phosphorylation into Smad 2, 3 and the like (obtaining transition ability into nucleus), (ii) dimer formation of Smad molecule, and (iii) discovering of inhibitor against the signal transfer pathway such as Smad 6, 7, or controlling of function of the pathway. However, because these pharmacofunctions are appeared in cytoplasm but not in ucleus and the pathway is well conserved, a screening method for pharmaceuticals based on such functions is not suitable to search pharmaceuticals with high specificity. Furthermore, other than the above (ii), the concrete interaction between molecules has not been clarified, and thus a theoretical approach for molecular designing based on the structure is not appropriate.
On the other hand, in connection with the transcription control by Smad molecule, the present inventor obtained the knowledge about the interaction of Smad molecule with intranuclear receptor or CBP/p300, thereby clarified a tangible partner of Smad. According to such knowledge, the present inventor developed a screening method for pharmaceuticals with specified site of action and high specificity. By using the above method, it becomes possible to find useful pharmaceutical candidates and to provide a guideline or molecular designing for synthesizing more useful materials. Based on such knowledge, pharmaceutical designing becomes possible. Various kinds of known techniques to determine the three dimensional structure such as X-ray crystallographic structure analysis, spectroscopic analysis such as NMR (nuclear magnetic resonance), IR(Infrared), and CD(circular dichroism), or various biological modification such as a point mutation techniques can reveal the three dimensional structure of the binding site of a Smad molecule and intranulcear receptor and transcription coupling factor. Thus obtained three dimensional structural data can be used to design pharmaceuticals, if necessary with a numerical calculating method such as a commercially available molecular modeling computer softwares (SYBYL(Tripos Inc.,St.Louis,USA); InsightII/Discover(Molecular Simulations Inc., San Diego, USA);Quanta/CHARMM(Molecular Simulations Inc., San Diego, USA);LOOK(Molecular Applications Group, Palo Alto, USA);CAChe(Oxford Molecular Group, Oxford, UK).
Furthermore, base on the above principle, it becomes possible to develop a screening method for an agonist or an antagonist of intranuclear receptor (for example, vitamin D receptor) with higher specificity. Since intranuclear receptors are distributed over various tissues, it is impossible to avoid some side effect of agonist or antagonist type pharmaceuticals screened by the prior method, which such intranuclear receptors are simply targeted. However, upon focusing on the interaction between Smad molecule and intranuclear receptors, according to the present invention, it is possible to inhibit or accelerate only the specific transcription control using Smad as a transcription coupling factor. Therefore, it becomes possible to search excellent pharmaceuticals with good efficiency and specificity (targeting various disease of bone, skin, liver, kidney, immune system, center system and the like, or benign tumor, malignant tumor, hyperplasia or fibrolysis) in addition to the known usefulness of intranuclear receptor agonist or antagonist.
In other words, the present invention provides a method to develop a novel therapeutic agent based on the novel knowledge of the interaction of Smad molecule with intranuclear receptor or with CBP/p300.
The present invention will be more fully understood from the detailed description given hereinbelow and the accompanying drawings, which are given by way of illustration only, and thus are not to be considered as limiting the present invention.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
REFERENCES:
patent: WO 95/30900 (1995
Kato Shigeaki
Yanagisawa Jun
Chugai Seiyaku Kabushiki Kaisha
Mertz Prema
Morgan & Lewis & Bockius, LLP
Murphy Joseph F.
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