207 results about "Proteasome" patented technology

Compounds and methods of selectively inhibiting an immunoproteasome are described. Also described are methods of treating a cancer, an inflammation, and / or an autoimmune disease and methods of suppressing endogenous antigenic peptide generation by administering to a subject in need of treatment thereof a therapeutic amount of an immunoproteasome specific inhibitor.

The present invention includes compounds that are useful in perturbing or disrupting the function of a transmembrane or intracellular protein, whereby binding of the compounds to the transmembrane or intracellular protein induces proteasomal degradation of the transmembrane or intracellular protein. The present invention further includes a method of inducing proteasomal degradation of a transmembrane or intracellular protein. The present invention further includes a method of identifying or validating a protein of interest as a therapeutic target for treatment of a disease state or condition.

Compounds that inhibit the activity of NF-κB or inhibit the activity of the proteasome or both promote bone formation and hair growth and are thus useful in treating osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyrdidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, and post-dental implantation; they also stimulate the production of hair follicles and are thus useful in stimulating hair growth, including hair density, in subject where this is desirable.

A continuous method for preparing proteosome-amphiphilic determinant vaccines for parenteral or mucosal administration using diafiltration or ultrafiltration technology. The amphiphilic determinants include lipopolysaccharides from gram negative bacteria, e.g. S. flexneri, P. shigelloides and S. sonnei. Proteosomes are obtained from group B type 2b meningococci. The active proteosome-amphiphilic determinant complexes (non-covalent complexes) of the vaccine are formed using diafiltration or ultrafiltration to remove the detergent under non-static conditions. The use of diafiltration or ultrafiltration decreases processing time and the opportunity for contamination and further permits the use of ambient temperature and efficient scale-up. In addition, the process permits the reliable and continuous monitoring of the dializate which enhances the efficiency of the entire process. The time of dialysis for the production of a lot of vaccine is reduced from 7-10 days to less than 72 hours and usually less than 48 or 24 hours. The use of the process optimizes the presence of each antigenic component in the preparation of multivalent vaccines.

Provided are previously uncharacterised markers of cancers, for example colorectal cancers, and uses of these as diagnostic and prognostic markers of cancers, and in particular colorectal cancers. The markers are SEQ ID NO: 1—hnRNP-K; SEQ ID NO:2—HMG-1; SEQ ID NO:3—proteasome subunit alpha type 1; SEQ ID NO:4—bifunctional purine biosynthesis protein; SEQ ID NO:5—ST11; SEQ ID NO:6—annex in IV; SEQ ID NO:7—60 kDa heat shock protein; SEQ ID NO:8—T complex protein 1 beta subunit; SEQ ID NO:9—T complex protein 1 epsilon subunit; SEQ ID NO: 10—mortalin; and SEQ ID NO: 11—TER-ATPase. The invention further provides related methods and materials for the use of the markers in therapeutic intervention in colorectal and other cancers e.g. to specifically target neoplastic cells without causing significant toxicity in healthy tissues, and to provide methods for the evaluation of the ability of candidate therapeutic compounds to modulate the biological activity of cancerous cells from the colon, rectum and other tissues.

Vif binds to APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Vif contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y / F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. Provided herein are methods of exploiting these discoveries to develop compounds useful to inhibit Vif degradation of APOBEC3G, and thereby inhibit viral infection and / or replication.

Compounds that inhibit the activity of the proteasome or the production of proteasomal proteins promote hair growth by stimulating the production of hair follicles, and are thus useful in stimulating hair growth, including hair density, in subject where this is desirable.

The invention relates to a circular agriculture system and an implementation method thereof. According to a characteristic that different biological wastes can be highly efficiently cycled by various insects and small animals, an insect breeding factory is constructed; and insect and small animal proteasome and insect feces residue organic fertilizer are respectively utilized as an animal factory protein feed and a plant factory organic fertilizer. Therefore, carious animal and plant products with high added values can be produced with high yields. With modern advanced agricultural technologies and equipment, stereo cultivation is usually carried out with rare species, such that a unit yield of the types of factories reaches more than a hundred times that of conventional agriculture. With the products from the three types of factories, a wide variety of series downstream industry chain group can be developed, such that best economic benefit can be ensured. The three types of factories, downstream industry chain spaces and farmer residential spaces can be arranged in a rise building. The buildings can form a highly clustered production, management, residence, agriculture, industry and business integral community. With farmland novel industry and landscape designs outside the buildings, a novel intensive town is formed.

Compounds, pharmaceutical compositions, and methods of using such compounds to treat or prevent diseases or disorders associated with or mediated by JAMM proteins are disclosed. The compounds and compositions inhibit the enzymatic activity of a JAMM domain, including the JAMM domain of the CSN5 subunit of the COP9-signalsome (CSN), the JAMM domain of the Rpn11 / Poh1 / Psmd14 subunit of the 26S proteasome, the JAMM domain of AMSH, the JAMM domain of AMSH-LP, the JAMM domain of BRCC36, among other JAMM domains.

The invention relates to crystalline peptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions.

The NF-E2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant defense and detoxification. To directly monitor stabilization of Nrf2 we fused its Neh2 domain, responsible for the interaction with its nucleocytoplasmic regulator, Keap1, to firefly luciferase (Neh2-luciferase). It is shown herein that Neh2 domain is sufficient for recognition, ubiquitination and proteasomal degradation of Neh2-luciferase fusion protein. The novel Neh2-luc reporter system allows direct monitoring of the adaptive response to redox stress and classification of drugs based on the time-course of reporter activation. The novel reporter was used to screen a library of compounds to identify activators of Nrf2. The most robust and yet non toxic Nrf2 activators found—nordihydroguaiaretic acid, fisetin, and gedunin-induced astrocyte-dependent neuroprotection from oxidative stress via an Nrf2-dependent mechanism.

Deuterated dipeptide boric acids or esters thereof, or crystal forms thereof, or pharmaceutically acceptable hydrates or solvates thereof are disclosed. The general structure of the compounds is shown as a formula (a) in the specification, wherein R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen, deuterium or halogens, or C1-C4 alkyl one or a plurality of or all hydrogen atoms of which are deuterated; and at least one of the R1, the R2, the R3, the R4, the R5 and the R6 is deuterated or deuterium. The compounds can effectively inhibit proteasomes and effectively treat or prevent cancer, cardiovascular disease, inflammation, immune disease, nephropathy, vasculogenesis or prostate disease.

The present invention is based on the discovery that inactivation of the heat shock response in cancer cells significantly enhances their sensitivity to proteasome and Hsp90 inhibitors. The inventors have discovered novel compounds which exhibit low toxicity, inhibit the heat shock protein response and sensitize cancer cells to anti-cancer therapies. In general, the heat shock protein inhibitors of the present invention share a common structure, namely a 2H-benzo[a]quinolizine tricyclic ring. Also encompassed are methods for a high throughput screen to identify heat shock inhibitors that sensitize cancer cells to anti-cancer therapies.

The present invention is directed to the identification of markers that can be used to determine whether patients with cancer are clinically responsive or non-responsive to a therapeutic regimen prior to treatment. In particular, the present invention is directed to the use of certain combinations of markers, wherein the expression of the markers correlates with responsiveness or non-responsiveness to a therapeutic regimen comprising proteasome inhibition. Thus, by examining the expression levels of individual markers and those comprising a marker set, it is possible to determine whether a therapeutic agent, or combination of agents, will be most likely to reduce the growth rate of tumors in a clinical setting.

Methods for making and using therapeutic formulations of Proteosome-based immunoactive compositions are provided. The immunogenic compositions, which include Proteosomes and liposaccharides, may be used to elicit or enhance a nonspecific innate immune response to, for example, treat or prevent infectious disease. In addition, after activating the innate immune system, immunogenic compositions further containing an antigen may be used to elicit a specific adaptive immune response. Furthermore, provided are compositions capable of altering hyperreactive responses or inflammatory immune responses, such as allergic reactions. Such compositions may be used as a prophylactic, or in various clinical settings to treat or prevent infectious disease (such as parasite, fungal, bacterial or viral infections), or to alter inappropriate inflammatory immune responses (such as allergic reactions or asthma).

Method and systems for determining if one or more animals has mastitis and for monitoring animals and the quality of the milk they produce are disclosed. Systems and test assays disclosed are used to determine the quantity of proteasomes and proteins thereof, the activity of proteasome enzymes, the quantity of proteasome bound and regulating proteins, and the quantity of ubiquinated protein. Components and reagents for use in the systems and assays are also disclosed.

Synthesis of many proteins is tightly controlled at the level of translation and plays an essential role in fundamental processes such as cell growth and proliferation, signaling, differentiation or death. Methods that allow imaging and identification of nascent proteins allow for dissecting regulation of translation, both spatially and temporally, including in whole organisms. Described herein are robust chemical methods for imaging and affinity-purifying nascent polypeptides in cells and in animals, based on puromycin analogs. Puromycin analogs of the present invention form covalent conjugates with nascent polypeptide chains, which are rapidly turned over by the proteasome and can be visualized and specifically captured by a bioorthogonal reaction (e.g., [3+2]cycloaddition). The methods of the present invention have broad applicability for imaging protein synthesis and for identifying proteins synthesized under various physiological and pathological conditions in vivo.

A skin care composition for stimulating selective catabolysis in cells of keratin surfaces comprising at least one autophagy activator and at least one proteasome activator, and a method for improving selective catabolysis in cells of keratin surfaces by treating with the composition.

An adjuvant complex composed of bacterial outer membrane protein proteosomes complexed to bacterial liposaccharide is prepared to contain the component parts under a variety of conditions. The complex can be formulated with antigenic material to form immunogenic compositions, vaccines and immunotherapeutics. An induced immune response includes protective antibodies and / or type 1 cytokines is shown for a variety of protocols.

The present invention provides a method for inducing apoptosis in selected cells by aggravating ER-stress. The aggravation of ER-stress is achieved in a specific manner by inhibiting SERCA (sarcoplasmic / endoplasmic reticulum calcium ATPase), leading to elevated level of cytoplasmic calcium concentration, yet without inhibiting the activity of COX-2 (cyclooxygenase-2) or triggering the release of histamine. Induction of apoptosis may be enhanced by first inducing or further aggravating ER-stress through inhibition of proteasome or proteases. Also provided are compounds and compositions useful as ER-stress aggravating agents, methods for screening, selecting, identifying and designing the same and methods for treating diseased conditions by inducing apoptosis through specific and selective aggravation of ER-stress.

Effective stimulation of immune responses is achieved through the use of a group A streptococcal antigen combined with proteosome adjuvant. The compositions are provided in particular for intranasal administration. The vaccine compositions are provided for use in inducing an immune response in an individual for the treatment or prophylaxis of group A streptococcal infection in an individual, preferably via prevention or reduction of colonisation of the throat following intranasal administration.

The invention discloses an inhibitor whose new compound and pharmaceutical composition can be used as proteasome. The compound of the invention can prevent three activities CT-L, T-L and PGPH of the proteasome, and can be used for treating various diseases related to proteasome.

The invention provides a method for separating an SARS coronavirus main proteinase inhibitor from a traditional Chinese medicine. The method comprises the following steps of: A. measuring the exosomatic suppressive activities of SARS coronavirus main proteinase inhibitors of various extractives from a single traditional Chinese medicine; B. selecting an extractive with the best exosomatic suppressive activity; and C. separating and selecting the extractives selected in the step B at least once. The compound separated by the method has exosomatic suppressive activities on SARS coronavirus mainproteinase, thereby being a possibly optimal medicament or a potential prodrug on sale.

The invention relates to tobacco ferredoxin capable of improving disease resistance of rice and a coding gene of the tobacco ferredoxin, and belongs to the field of disease-resistant genetic engineering of the rice. Tobacco ferredoxin Ferredoxin (NbFd) in effector protein XopL mediated plant cells generates ubiquitination, then the tobacco ferredoxin is degraded by proteasomes, and the number of plant cell chloroplasts entering the NbFd is reduced, so that transmission of electrons in photosynthesis is restrained, accumulation of active oxygen is caused, and plants are induced to produce an allergic reaction (HR) type disease-resistant reaction. Ferredoxin protein in the rice does not interact with XopL, but after Ferredoxin protein coding genes from tobacco are transferred into the rice,the resistance of the rice to bacterial leaf spot can be improved. The tobacco Ferredoxin protein coding gene NbFd obtained in the way of protein interaction can be used as a breeding gene resource ofthe rice for resisting bacterial leaf spots, and the resistance of obtained NbFd transgenic rice to the bacterial leaf spots can be notably improved.

Methods of treating, ameliorating, preventing, or reducing the risk of developing an auto-immune disease and / or an inflammatory condition, such as systemic lupus erythematosus, in a patient, such as a human being, using a therapeutically effective amount of an agent(s) that inhibits the activity of one or more of histone deacetylase (HDAC), IKB kinase (IKK-2), nuclear factor kB (NF-kB), ubiquitin / proteasome and Janus kinase (JAK) are disclosed. Compounds useful in such methods are also presented.

An immunogenic complex, essentially consisting of neisserial outer membrane protein proteosomes hydrophobically complexed to native purified bacterial lipopolysaccharide and formulated in accordance with the current invention for mucosal delivery such as via the oral or intranasal route is used as a vaccine. Specifically, a vaccine using shigella lipopolysaccharides complexed to proteosomes for such mucosal administration induces IgG and IgA antibodies in sera and in respiratory and intestinal fluids. Furthermore, such antibodies are associated with protection against shigella infection and these vaccines are herein demonstrated to protect against mucosal infection with shigella.

The invention discloses an application of PA200 proteins in preparation of products. The products have at least one of the following functions from (1) to (4): (1) combining with acetylated proteins; (2) promoting the degradation of the acetylated proteins; (3) participating in repair of DNA (deoxyribonucleic acid) damages of somatic cells; and (4) participating in the formation of sperms. The invention has breakthroughs in four following aspects: (1) finding a mechanism of regulation and control of degradation of the histones, the sperm formation and the DNA repair by acetylation; (2) revealing the degradation of the histones medicated by acetylation rather than ubiquitination through PA200 / Blm10 proteasome; (3) finding novel testis-specific proteasome containing PA200 and alpha 4s, and revealing the core histones as a first type biological substrate for the proteasome; and (4) revealing that a histone deacetylase inhibitor can promote the degradation of the histones which are induced by DNA double-strand breaks and medicated by acetylation, enhance the sensitivity of cells to DNA damages and easily lead to the death of the cells.

The present invention provides a method for inducing apoptosis in selected cells by aggravating ER-stress. The aggravation of ER-stress is achieved in a specific manner by inhibiting SERCA (sarcoplasmic / endoplasmic reticulum calcium ATPase), leading to elevated level of cytoplasmic calcium concentration, yet without inhibiting the activity of COX-2 (cyclooxygenase-2) or triggering the release of histamine. Induction of apoptosis may be enhanced by first inducing or further aggravating ER-stress through inhibition of proteasome or proteases. Also provided are compounds and compositions useful as ER-stress aggravating agents, methods for screening, selecting, identifying and designing the same and methods for treating diseased conditions by inducing apoptosis through specific and selective aggravation of ER-stress.