- Analysis of subpocket selectivity and identification of potent selective inhibitors for matriptase and matriptase-2
-
We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes.
- Duchêne, Dominic,Colombo, Elo?c,Désilets, Antoine,Boudreault, Pierre-Luc,Leduc, Richard,Marsault, Eric,Najmanovich, Rafael
-
-
Read Online
- Inhibitors of HGFA, matriptase, and hepsin serine proteases: A nonkinase strategy to block cell signaling in cancer
-
Hepatocyte growth factor activators (HGFA), matriptase, and hepsin are S1 family trypsin-like serine proteases. These proteases proteolytically cleave the single-chain zymogen precursors, pro-HGF (hepatocyte growth factor), and pro-MSP (macrophage stimula
- Han, Zhenfu,Harris, Peter K. W.,Jones, Darin E.,Chugani, Ryan,Kim, Tommy,Agarwal, Manjula,Shen, Wei,Wildman, Scott A.,Janetka, James W.
-
-
Read Online
- Discovery of Selective Matriptase and Hepsin Serine Protease Inhibitors: Useful Chemical Tools for Cancer Cell Biology
-
Matriptase and hepsin belong to the family of type II transmembrane serine proteases (TTSPs). Increased activity of these and the plasma protease, hepatocyte growth factor activator (HGFA), is associated with unregulated cell signaling and tumor progression through increased MET and RON kinase signaling pathways. These proteases are highly expressed in multiple solid tumors and hematological malignancies. Herein, we detail the synthesis and structure-activity relationships (SAR) of a dipeptide library bearing Arg α-ketobenozothiazole (kbt) warheads as novel inhibitors of HGFA, matriptase, and hepsin. We elucidated the substrate specificity for HGFA using positional scanning of substrate combinatorial libraries (PS-SCL), which was used to discover selective inhibitors of matriptase and hepsin. Using these selective inhibitors, we have clarified the specific role of hepsin in maintaining epithelial cell membrane integrity, known to be lost in breast cancer progression. These selective compounds are useful as chemical biology tools and for future drug discovery efforts.
- Damalanka, Vishnu C.,Han, Zhenfu,Karmakar, Partha,O'Donoghue, Anthony J.,La Greca, Florencia,Kim, Tommy,Pant, Shishir M.,Helander, Jonathan,Klefstr?m, Juha,Craik, Charles S.,Janetka, James W.
-
-
Read Online
- SELECTIVE TMPRSS2 INHIBITORS AND MEDICAL USE THEREOF
-
The invention relates to the compound of general formula (I) as novel inhibitors of TMPRSS2 and their use for the prophylaxis and treatment of influenza virus infection or coronavirus infection, in particular, SARS-CoV2 (COVID-19) infection.
- -
-
Paragraph 0118-0119
(2021/12/31)
-
- MATRIPTASE INHIBITORS AND USES THEREOF AGAINST ORTHOMYXOVIRIDAE INFECTIONS
-
The present invention provides matriptase inhibitors and compositions for treating and preventing orthomyxovirus infections such as flu infections. The present invention also provides novel compounds, compositions, methods of use, uses and kits thereof for inhibiting matriptase. Such compounds are useful for treating and preventing orthomyxovirus infections, such as flu infections, and for inhibiting tumor growth, progression and/or metastasis.
- -
-
Paragraph 0304
(2016/05/02)
-
- INHIBITORS OF GROWTH FACTOR ACTIVATION ENZYMES
-
The present invention generally relates to compounds that are useful for inhibiting one or more of hepatocyte growth factor activator, matriptase, hepsin, Factor Xa, or thrombin. The present invention also relates to various methods of using the inhibitor compounds including treating a malignancy, a pre-malignant condition, or cancer by administering an effective amount of the inhibitor to a subject in need thereof.
- -
-
Paragraph 0081; 0187
(2016/09/26)
-
- Design and synthesis of potent, selective inhibitors of matriptase
-
Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1-P4 substrate recognition sequence of the enzyme. Preliminary structure-activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.
- Colombo, Eloic,Desilets, Antoine,Duchene, Dominic,Chagnon, Felix,Najmanovich, Rafael,Leduc, Richard,Marsault, Eric
-
supporting information; experimental part
p. 530 - 534
(2012/08/29)
-
- Total synthesis of miraziridine A and identification of its major reaction site for cathepsin B
-
The synthesis of miraziridine A, a pentapeptide derivative isolated from marine sponge, and its truncated analogs has been achieved. To construct the backbone of miraziridine A, a side-chain-unprotected vinylogous arginine was condensed with an aziridine-
- Konno, Hiroyuki,Kubo, Kanako,Makabe, Hidefumi,Toshiro, Emi,Hinoda, Naoyuki,Nosaka, Kazuto,Akaji, Kenichi
-
p. 9502 - 9513
(2008/02/12)
-
- Compounds and Compositions as Channel Activating Protease Inhibitors
-
The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating channel activating proteases, and methods for using such compounds to treat, ameliorate or prevent a condition associated with a channel activating protease, including but not limited to prostasin, PRSS22, TMPRSS11 (e.g., TMPRSS11B, TMPRSS11E), TMPRSS2, TMPRSS3, TMPRSS4 (MTSP-2), matriptase (MTSP-1), CAP2, CAP3, trypsin, cathepsin A, or neutrophil elastase.
- -
-
Page/Page column 12-13
(2008/06/13)
-
- Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants
-
Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa
- Lin, Jian,Deng, Hongfeng,Jin, Lei,Pandey, Pramod,Quinn, Jesse,Cantin, Susan,Rynkiewicz, Michael J.,Gorga, Joan C.,Bibbins, Frank,Celatka, Cassandra A.,Nagafuji, Pamela,Bannister, Thomas D.,Meyers, Harold V.,Babine, Robert E.,Hayward, Neil J.,Weaver, David,Benjamin, Howard,Stassen, Frans,Abdel-Meguid, Sherin S.,Strickler, James E.
-
p. 7781 - 7791
(2007/10/03)
-
- In-depth study of tripeptide-based α-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1′ subsite and its implications to structure-based drug design
-
Thrombin inhibitors are potentially useful in medicine for their anticoagulant and antithrombotic effects. We synthesized and evaluated diverse heterocycle-activated ketones based on the D-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors. The peptide-based α-ketoheterocycles were typically prepared by either an imidate or a Weinreb amide route (Schemes 1 and 2), the latter of which proved to be more general. Test compounds were generally assayed for inhibition of human α-thrombin and bovine trypsin. From a structure-based design standpoint, the heterocycle allows one to explore and adjust interactions within the S1′ subsite of thrombin. The preferred α-ketoheterocycle is a π-rich 2-substituted azole with at least two heteroatoms proximal to the carbon bearing the keto group, and a preferred thrombin inhibitor is 2-ketobenzothiazole 3, with a potent Ki value of 0.2 nM and ca. 15-fold selectivity over trypsin. 2-Ketobenzothiazole 13 exhibited exceedingly potent thrombin inhibition (Ki = 0.000 65 nM; slow tight binding). Several α-ketoheterocycles had thrombin Ki values in the range 0.1-400 nM. The "Arg" unit in the α-ketoheterocycles can be sensitive to stereomutation under mildy basic conditions. For example, 2-ketothiazoles 4 and 59 readily epimerize at pH 7.4, although they are fairly stable stereochemically at pH 3-4; thus, suitable conditions had to be selected for the enzymatic assays. Lead D-Phe-Pro-Arg 2-benzothiazoles 3, 4, and 68 displayed good selectivity for thrombin over other key coagulation enzymes (e.g., factor Xa, plasmin, protein Ca, uPA, tPA, and streptokinase); however, their selectivity for thrombin over trypsin was modest (50 = 30-40 nM). They also proved to be potent anticoagulant/ antithrombotic agents in vivo on intravenous administration, as determined in the canine arteriovenous shunt (ED50 = 0.45-0.65 mg/kg) and the rabbit deep vein thrombosis (ED50 = 0.1-0.4 mg/kg) models. Intravenous administration of 3, and several analogues, to guinea pigs caused hypotension and electrocardiogram abnormalities. Such cardiovascular side effects were also observed with some nonguanidine inhibitors and inhibitors having recognition motifs other than D-Phe-Pro-Arg. 2-Benzothiazolecarboxylates 4 and 68 exhibited significantly diminished cardiovascular side effects, and benzothiazolecarboxylic acid 4 had the best profile with respect to therapeutic index. The X-ray crystal structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S1′ region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate of 4 forms a salt bridge with the side chain of Lys-60F such that it adopts an extended anti conformation. Since 3 has a 10-fold greater affinity for thrombin than does 4, any increase in binding energy resulting from this salt bridge is apparently offset by perturbations across the enzyme (viz. Figure 4). The increased affinity and selectivity of 2-ketobenzothiazole inhibitors, such as 3, may be primarily due to the aromatic stacking interaction with Trp-60D. However, energy contour calculations with the computer program GRID also indicate a favorable interaction between the benzothiazole sulfur atom and a hydrophobic patch on the surface of thrombin.
- Costanzo, Michael J.,Almond Jr., Harold R.,Hecker, Leonard R.,Schott, Mary R.,Yabut, Stephen C.,Zhang, Han-Cheng,Andrade-Gordon, Patricia,Corcoran, Thomas W.,Giardino, Edward C.,Kauffman, Jack A.,Lewis, Joan M.,De Garavilla, Lawrence,Haertlein, Barbara J.,Maryanoff, Bruce E.
-
p. 1984 - 2008
(2007/10/03)
-
- Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone
-
Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a Ki value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (Ki = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-? resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.
- Costanzo, Michael J.,Yabut, Stephen C.,Almond Jr., Harold R.,Andrade-Gordon, Patricia,Corcoran, Thomas W.,De Garavilla, Lawrence,Kauffman, Jack A.,Abraham, William M.,Recacha, Rosario,Chattopadhyay, Debashish,Maryanoff, Bruce E.
-
p. 3865 - 3876
(2007/10/03)
-