39 results about "Stapled peptide" patented technology

The invention relates to the field of biological medicine, in particular to a stapled peptide targeting RAS-Raf protein interaction and application of the stapled peptide, the stapled peptide is obtained in the mode that Ac-SLHDCLMKALKVR-NH2 and Ac-SLHDCLMKALKVRGL-NH2 serve as peptide chain templates, amino acid at the i site and amino acid at the (i + 4) site are replaced with S5 and cyclized, and the nitrogen terminal is further modified with stearic acid. The stapled peptide can effectively inhibit proliferation and migration of tumor cells; the serum stability is high, and meanwhile, the cell transmembrane capability is excellent, so that target protein in cells can be better targeted, and the biological function of the target protein can be exerted. Therefore, the alphaH helical conformation of the RBD of the RAF can be stabilized through the stapled peptide and a nitrogen-terminal fatty acid modification strategy, the membrane permeability and stability of the RAF are improved, the binding force of the RAF and RAS is further improved, and proliferation and migration of various tumor cells are inhibited.

The invention discloses a decafluorobiphenyl-based Tat47-57 binding peptide, the amino acid sequence of the binding peptide is shown as SEQ ID NO.1 or SEQ ID NO.2, the fourth amino acid and the eighth amino acid of the SEQ ID NO.1 are bound through decafluorobiphenyl, and the fifth amino acid and the twelfth amino acid of the SEQ ID NO.2 are bound through decafluorobiphenyl. In particular, the decafluorobiphenyl-based Tat47-57 binding peptides (P3 and P6) are efficient CPPs, capable of delivering a variety of cargo molecules into the cytoplasm of mammalian cells. Meanwhile, decafluorobiphenyl cyclization plays a key role in cellular uptake and endosome escape. The two peptides P3 and P6 show remarkable cell permeability, and are speculated to enter cells through gridding protein dependent endocytosis. They also show efficient endosome escape ability, and have successfully applied P3 and P6 as CPPs to deliver phospholipid peptides and avidin.

Methods and compositions are provided for extending the half-life of a therapeutic agent. A modified therapeutic agent (mTA) comprises a therapeutic agent, a staple, and a half-life extending molecule. The mTAs disclosed herein may be used to treat a disease or a condition in a subject in need thereof.

The invention discloses an application of a Beclin 1 targeting pharmaceutical composition in preparation of antitumor drugs. The pharmaceutical composition comprises stapled peptides targeting Beclin 1 and platinum chemotherapeutic drugs. The treatment effect of the pharmaceutical composition on ovarian cancer is verified through an in-vitro cell model and an in-vivo mouse model, the combined use of the stapled peptide i7-01s-31 targeting Beclin 1 and cis-platinum can further amplify the anti-tumor effect of the stapled peptide i7-01s-31 and cis-platinum, the synergistic interaction effect is achieved, and the pharmaceutical composition can be used for treating ovarian cancer. The problem that drug resistance is easily generated due to single use of cis-platinum in actual clinical application is avoided; meanwhile, the dosage of chemotherapeutic drugs can be reduced through drug combination, so that the treatment safety is improved, and the toxicity is reduced.

The application discloses a stapled peptide compound for selectively degrading MYC protein, a preparation method and application thereof; the compound is sequentially connected in the N-terminal to C-terminal direction by a peptide recognition segment, a flexible linker and a chaperone-mediated autophagy recognition motif KFERQ or a similar motif; the peptide recognition segment is introduced by an (i, i+7) site alkenyl amino acid and a Grubbs catalytic RCM reaction to form a full carbon hydrogen stapling bridge to stabilize the alpha-helix conformation; stapled modification of a typical compound MAX-7 significantly improves the alpha-helix content, the protease stability and the cell penetration, so that the compound can efficiently enter cells and be located in lysosomes, and MYC protein is selectively degraded through the CMA pathway; in-vitro experiments show that MAX-7 can inhibit the proliferation, migration and invasion of various MYC-driven tumor cells, and induce apoptosis; the application provides a brand-new lysosome-directed degradation strategy for the "undruggable" target MYC, and establishes a universal technical platform which can be popularized to other difficult drug proteins.

The present disclosure provides powerful technologies for the development, production, characterization, and / or use of stapled peptide compositions. Among other things, the present disclosure provides strategies for defining amino acid sequences particularly amenable or useful for stapling, as well as technologies, reagents, and systems for developing, producing, characterizing, and / or using stapled peptides having such amino acid sequences.

Methods and compositions are provided for extending the half-life of a therapeutic agent A modified therapeutic agent (mTA) comprises a therapeutic agent, a staple, and a half-life extending molecule. The mTAs disclosed herein may be used to treat a disease or a condition in a subject in need thereof.

The invention belongs to the field of polypeptide medicines, and particularly relates to stapled peptide and application thereof. According to the present invention, Ac-LKRVWKRVFKLLKS5YWRS5LKKPVR-NH2 is adopted as a peptide chain template, and an amino acid residue 15Y is replaced by K so as to obtain the target stapled peptide SLP-8; compared with the template polypeptide, the hemolytic activity of the obtained stapled peptide SLP-8 is obviously improved.

The application discloses a kind of double S-alkyl isothiourea derivatives, its preparation method and application, belong to biochemical technical field.The double S-alkyl isothiourea derivative is the compound shown in general formula 1 or its pharmaceutically acceptable salt, in formula, R is saturated alkane or unsaturated alkane;X is any one of i, ii and iii;I is branched C1-C 20 Saturated alkane or straight-chain C1-C 20 Saturated alkane;II is unsaturated alkane;III is heteroatom-substituted alkane.The application further discloses a preparation method and application of the above-mentioned double S-alkyl isothiourea derivative, a stapled peptide and a preparation method thereof.The double S-alkyl isothiourea derivative of the application can be used for stapled peptide synthesis, and the obtained stapled peptide containing guanidyl structure has the advantages of good water solubility and strong membrane permeability in addition to various advantages of traditional all-carbon hydrogen stapled peptide in polypeptide structure modification.

Provided herein are stapled peptide-antibody conjugates (SPACs) comprising a stapled peptide conjugated to an antibody or antigen-binding fragment thereof. In certain embodiments, the stapled peptide is conjugated to the antibody or antigen-binding fragment thereof via a linker. In certain embodiments, the SPACs provided herein can be used to deliver stapled peptides to cells (e.g., cancer cells) with relatively high selectivity and relatively low off-target toxicity. Also provided herein are pharmaceutical compositions and kits comprising the SPACs described herein, methods of using the same (e.g., to treat cancer and / or inhibit tumor growth in a subject), and methods of preparing the same.

The present invention belongs to the field of polypeptide drugs, and specifically relates to a glycosylated bicyclic stapled peptide that can improve the anti-drug-resistant bacteria activity, improve the serum stability, and has good enzymatic hydrolysis stability on the basis of a template polypeptide, and its application. The present invention modifies the amino acid sequence of the template polypeptide SLP-0: Ac-LKRVWKRVFKLLKRYWRQLKKPVR-NH2 to obtain a glycosylated bicyclic stapled peptide. Compared with the template polypeptide SLP-0, its antibacterial effect is significantly improved, especially the antibacterial performance against Klebsiella pneumoniae (KP) is increased by 31 times compared with the template peptide SLP-0. Among them, SLP-51 has significant stability against trypsin, chymotrypsin and serum.

The application discloses a stapling peptide targeting TRIB3 / SSRP1 interaction and application of the stapling peptide in preparation of anti-multiple myeloma drugs. Through a series of experiments such as immunoprecipitation coupling mass spectrometry, it is found that TRIB3 directly interacts with SSRP1 protein in multiple myeloma cells, thereby playing a role in promoting malignant proliferation of multiple myeloma, and TRIB3 promotes degradation of the SSRP1 protein through a ubiquitin-proteasome pathway. The stapling peptide 7695-SP5 inhibits malignant proliferation of multiple myeloma by specifically inhibiting TRIB3 / SSRP1 protein interaction. The stapling peptide 7695-SP5 can be used as a TRIB3 / SSRP1 protein interaction inhibitor to treat diseases caused by increased expression of TRIB3 and SSRP1 proteins, such as multiple myeloma, and is expected to be developed into a novel anti-tumor drug.

The present disclosure relates to a biochemical field, and provides a polypeptide, the polypeptide includes: (I), an amino acid sequence as shown in any one of SEQ ID No.1, SEQ ID No.4, and SEQ ID No.5; or (II), an amino acid sequence obtained by substituting, deleting, or adding one or more amino acids to the amino acid sequence of (I), and having a same function as the amino acid sequence of (I); or (III) an amino acid sequence with greater than 80% similarity to the amino acid sequence of (I) or (II); or (IV) a cell-penetrating polypeptide obtained by combining the polypeptide of (I), (II), or (III) with a cell-penetrating peptide; or (V) a stapled peptide obtained by stapling the polypeptide of (I), (II), or (IV). The polypeptide has a significant inhibitory effect on methylation and METTL3 expression. A preparation method and use of the polypeptide are further provided.

The invention belongs to the field of polypeptide drugs, and particularly relates to an antibacterial polypeptide and application thereof. According to the invention, Rink amide MBHA amino resin is used as a solid phase carrier, modification and transformation are carried out according to an amino acid sequence of a template polypeptide raniseptinPL: Ac-GVFDTVKKIGKAVGKFALGVAKNYLNS-NH2, and on the basis of retaining key amino acid residues, original amino acids are respectively replaced by S5 and R8 at amino acid positions i, i + 4 and i and i + 7, so that a target stapling peptide is obtained. Compared with a template polypeptide PL-0, the obtained stapled peptide has the advantage that the antibacterial activity on staphylococcus aureus, enterococcus faecium, enterococcus faecalis and staphylococcus epidermidis can be obviously improved.

The invention relates to stable peptide-mediated targeted protein degradation. Specifically, the invention relates to a chimera, and more specifically relates to a nailing peptide degradation determinant chimera. The present invention relates to a protein fusion protein that acts as a protein degradation inducing moiety by binding a nailing peptide that binds to a disease-related protein to a small molecule degradation determinant (e.g., a cereblone-or VHL-binding small molecule as a degradation determinant) or a polypeptide sequence degradation determinant (e.g., a Cop1-binding Trib peptide as a degradation determinant); or by binding a stapling peptide degradation determinant to a peptide (e.g., a stapling peptide) or a small molecule bound to a disease-associated protein to act as a protein degradation inducing moiety. The present application also relates to methods of targeted degradation of endogenous proteins by using a stapling peptide degradation determinant chimera that can be used to treat proliferative diseases or other conditions, where elimination of a disease-causing or disease-associated protein may have a therapeutic benefit. The invention also provides a method for preparing the compounds and intermediates thereof.

The invention belongs to the field of polypeptide drugs, and particularly relates to a stapling peptide with an antibacterial effect and application thereof. According to the present invention, Ac-LKRVWKRVFKLLKS5YWRS5LKKPVR-NH2 is adopted as a peptide chain template, and an amino acid residue 11L is replaced by K so as to obtain the target stapled peptide SLP-6; compared with the template polypeptide, the hemolytic activity of the obtained stapled peptide SLP-6 is obviously improved.

The application belongs to the field of polypeptide drugs, and particularly relates to an antibacterial polypeptide and application thereof in pharmacy. The application takes Rink amide MBHA amino resin as a solid phase carrier, and modifies and transforms according to a template polypeptide raniseptin PL:Ac-GVFDTVKKIGKAVGKFALGVAKNYLNS-NH2 amino acid sequence, wherein amino acid residues 19G and 26N are replaced by R8 and S5, to obtain a target stapled peptide PL-16. The stapled peptide PL-16 can significantly improve the antibacterial activity on Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis and Staphylococcus epidermidis relative to the template polypeptide PL-0.

The invention belongs to the technical field of polypeptide drugs, and particularly relates to a series of polypeptides with an anti-cancer effect and application thereof. According to the invention, Rink amide MBHA amino resin is used as a solid phase carrier, modification is carried out according to an amino acid sequence of a template polypeptide Hymenochirin-1Pa (H-0): Ac-LKLSPKTKDTLKKVLKGAIKGAIAIASAMA-NH2, and on the basis of retaining key amino acid residues, original amino acids are replaced by R8 and S5 at the positions of i and i + 7 amino acids, so that the target stapling peptide is obtained. Compared with a template polypeptide H-0, the obtained stapled peptide has the advantage that the anti-tumor activity on human liver cancer cells Huh7, human non-small cell lung cancer cells A549, glioma cells U87 and colon cancer cells T84 can be obviously improved.

A pharmaceutical combination having one or more MDM2 inhibitor and one or more inhibitor of dephosphorylation of elF2α. MDM2 inhibitors are non-peptide small molecule inhibitors or stapled peptide inhibitors of the interaction between MDM2 and p53. Inhibitors of phosphorylation of elF2α are non-peptide small molecule inhibitors. Components of the pharmaceutical combination are administered to a subject in need thereof in a combined therapeutic amount to provide therapeutic effect and optionally synergistic therapeutic effect. A method for treatment of proliferative disease or disorders, including various cancers, which comprises administering to a subject in need thereof of one or more MDM2 inhibitor and one or more inhibitor of dephosphorylation of elF2α, wherein the inhibitors are administered in a combined therapeutic amount to provide therapeutic effect and optionally synergistic therapeutic effect.

This disclosure relates to chimeras comprising a stapled peptide conjugated to a compound that binds a protein (e.g., a protein that is involved in or that is causative of disease, e.g., cancer) (e.g., a compound that binds to a BET protein, e.g., JQ1), also referred to herein as Stapled Peptide-PROteolysis Targeting Chimeras (SP-PROTACs), and related compositions and uses thereof, e.g., in the treatment of a disease (e.g., a cancer or other disease driven by or related to the protein to which the compound binds). The chimeras act as combined protein degradation-inducing and protein targeting and moieties, e.g., stapled peptide to recruit the degradation protein such as HDM2 (and target HDMX to maximally reactivate p53) and a small molecule to engage a protein (e.g., a protein that is involved in or that is causative of a disease, e.g., a cancer).

The invention belongs to the field of polypeptide drugs, and particularly relates to an antibacterial stapling peptide and application thereof. According to the present invention, Ac-LKRVWKRVFKLLKS5YWRS5LKKPVR-NH2 is adopted as a peptide chain template, and an amino acid residue 12L is replaced by K so as to obtain the target stapled peptide SLP-7; compared with the template polypeptide, the hemolytic activity of the obtained stapled peptide SLP-7 is obviously improved.

The invention relates to the technical field of polypeptide compounds, in particular to a stapled peptide compound, a preparation method and application thereof and a skin care product. The structural formula of the stapled peptide compound is shown in the specification. The polypeptide has high anti-enzymolysis stability, can significantly improve the expression ability of up-regulated fiber cells and promote the expression of collagen, and can be used in the fields of wrinkle resistance, aging resistance, repair and the like.

The invention relates to the technical field of polypeptide compounds, in particular to a stapled peptide compound, a preparation method and application thereof and a skin care product. The structural formula of the stapled peptide compound is shown in the specification. The polypeptide has high anti-hydrolysis stability, can significantly improve the expression ability of up-regulated fiber cells and promote the expression of collagen, and can be used in the fields of wrinkle resistance, aging resistance, repair and the like.

The present disclosure provides novel polypeptide conjugates. The polypeptide conjugates disclosed herein comprise a stapled peptide, which comprises a peptide and at least one staple that holds the peptide in an α-helical structure, and a cyclic cell-penetrating peptide (cCPP) conjugated directly or indirectly to the stapled peptide. The present disclosure demonstrates that the cCPP can be used to confer consistent cell permeability to the stapled peptide.

Stapled peptides and mutant BCL-2 family peptides and compositions comprising the same are provided. Also provided are methods of using the stapled peptides and mutant BCL-2 family peptides for selectively protecting sensory neurons from age-related and / or chemotherapy induced axonal degeneration in a human subject in need thereof, treating or preventing chemotherapy induced peripheral neuropathy (CIPN) in a human subject in need thereof, averting neuropathic side effects of chemotherapy and / or other causes of axonal degeneration in a human subject in need thereof, and treating or preventing hearing loss in a human subject in need thereof. The methods involve administering to the human subject a stapled peptide and a mutant BCL-2 family peptide disclosed herein.

Stapled peptides and mutant BCL-2 family peptides and compositions comprising the same are provided. Also provided are methods of using the stapled peptides and mutant BCL-2 family peptides for selectively protecting sensory neurons from age-related and / or chemotherapy induced axonal degeneration in a human subject in need thereof, treating or preventing chemotherapy induced peripheral neuropathy (CIPN) in a human subject in need thereof, averting neuropathic side effects of chemotherapy and / or other causes of axonal degeneration in a human subject in need thereof, and treating or preventing hearing loss in a human subject in need thereof. The methods involve administering to the human subject a stapled peptide and a mutant BCL-2 family peptide disclosed herein.

This disclosure relates to chimeras comprising a stapled peptide conjugated to a compound that binds a protein (e.g., a protein that is involved in or that is causative of disease, e.g., cancer) (e.g., a compound that binds to a BET protein, e.g., JQ1), also referred to herein as Stapled Peptide-PROteolysis Targeting Chimeras (SP-PROTACs), and related compositions and uses thereof, e.g., in the treatment of a disease (e.g., a cancer or other disease driven by or related to the protein to which the compound binds). The chimeras act as combined protein degradation-inducing and protein targeting and moieties, e.g., stapled peptide to recruit the degradation protein such as HDM2 (and target HDMX to maximally reactivate p53) and a small molecule to engage a protein (e.g., a protein that is involved in or that is causative of a disease, e.g., a cancer).

Peptides useful as inflammasome inhibitors are disclosed and can comprise an H2 helix of a pyrin domain, wherein at least two non-consecutive amino acids of the H2 helix are covalently linked. Methods of treating a subject with a disease comprising administering to the subject the disclosed peptides are also disclosed. Further, disclosed herein are methods of inhibiting binding between a first polypeptide comprising a pyrin domain and a second polypeptide comprising a pyrin domain, the method comprising contacting either the first polypeptide or the second polypeptide with the disclosed peptides.