公开(公告)号：US10667935B2

公开(公告)日：2020-06-02

申请号：US16035241

申请日：2018-07-13

Applicant: NOVARTIS AG

Inventor： Qi-Ying Hu ,  Hidetomo Imase

IPC: A61K9/00 ,  A61F5/00 ,  A61K47/54 ,  A61K47/64 ,  A61K47/68 ,  A61C5/90 ,  A61F5/56

Abstract: The invention provides methods to prepare protein conjugates from proteins having at least two cysteines. In one embodiment, a protein with a disulfide linkage is reduced to provide two free cysteines for reaction with a 1,3-dihaloacetone or similar reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form a Schiff base to an aminated payload molecule, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant. The linkage between the sulfur atoms in each case holds the protein or peptide in a constrained conformation, while also providing a convenient place for attaching a payload with good specificity and efficiency.

公开(公告)号：US09982017B2

公开(公告)日：2018-05-29

申请号：US14714914

申请日：2015-05-18

Applicant: Novartis AG

Inventor： Frederic Zecri ,  Andrei Golosov ,  Philipp Grosche ,  Hongjuan Zhao ,  Qi-Ying Hu ,  Hidetomo Imase

IPC: A61K38/10 ,  C07K7/08 ,  C07K7/56 ,  C07K7/60 ,  A61K38/00

CPC classification number: A61M16/0816 ,  A61K38/00 ,  A61K38/10 ,  A61M16/0066 ,  A61M16/201 ,  A61M2016/0027 ,  A61M2016/003 ,  A61M2205/35 ,  A61M2205/502 ,  C07K7/08 ,  C07K7/56 ,  C07K7/60

Abstract: The invention provides a synthetic polypeptide of Formula I′: or an amide, an ester or a salt thereof, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12 and X13 are defined herein. The polypeptides are agonist of the APJ receptor. The invention also relates to a method for manufacturing the polypeptides of the invention, and its therapeutic uses such as treatment or prevention of acute decompensated heart failure (ADHF), chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes (including gestational diabetes), obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries (including sunburn) and preeclampsia. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

公开(公告)号：US11311400B2

公开(公告)日：2022-04-26

申请号：US16850920

申请日：2020-04-16

Applicant: NOVARTIS AG

Inventor： Qi-Ying Hu ,  Hidetomo Imase

IPC: A61K9/00 ,  A61F5/00 ,  A61K47/54 ,  A61K47/64 ,  A61K47/68 ,  A61C5/90 ,  A61F5/56

Abstract: The invention provides methods to prepare protein conjugates from proteins having at least two cysteines. In one embodiment, a protein with a disulfide linkage is reduced to provide two free cysteines for reaction with a 1,3-dihaloacetone or similar reactant, linking the sulfur atoms of the two cysteines together. The ketone inserted between the sulfur atoms is then used to form a Schiff base to an aminated payload molecule, thus conjugating the protein to a payload. In another embodiment, two cysteine residues are tied together by reaction with a 1,3-dihaloacetone or similar reactant. The linkage between the sulfur atoms in each case holds the protein or peptide in a constrained conformation, while also providing a convenient place for attaching a payload with good specificity and efficiency.