Potent and Selective Thrombin Inhibitors Incorporating the Constrained Arginine Mimic <scp>l</scp>-3-Piperidyl(<i>N</i>-guanidino)alanine at P<sub>1</sub>

Oe, Levy; Je, Semple; Ml, Lim; Reiner, John; We, Rote; Dempsey, Edward C.; Bm, Richard; Zhang, E; Tulinsky, A.; Wc, Ripka; Rf, Nutt

doi:10.1021/jm960607j

Cited by 33 publications

(11 citation statements)

References 17 publications

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“…Research to date with peptidomimeticstrand mimetic scaffolds has predominately focused on inhibiting protease-protein substrate interactions. These studies include the synthesis of inhibitory agents containing various ring systems including six-membered piperidone rings, 27 [87,88], pyridone rings, 28 [89], and pyrrolinone rings, 29 [90] incorporated into peptide backbones, as well as the use of cyclic urea complexes, 30 [91][92][93], as depicted in Fig. (14).…”

Section: Peptidomimetic -Strand Mimetic Scaffoldsmentioning

confidence: 99%

Scaffolds for Blocking Protein-Protein Interactions

Hershberger¹,

Lee²,

Chmielewski

2007

CTMC

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Due to the pivotal roles that protein-protein interactions play in a plethora of biological processes, the design of therapeutic agents targeting these interactions has become an attractive and important area of research. The development of such agents is faced with a variety of challenges. Nevertheless, considerable progress has been made in the design of proteomimetics capable of disrupting protein-protein interactions. Those inhibitors based on molecular scaffold designs hold considerable interest because of the ease of variation in regard to their displayed functionality. In particular, protein surface mimetics, alpha-helical mimetics, beta-sheet/beta-strand mimetics, as well as beta-turn mimetics have successfully modulated protein-protein interactions involved in such diseases as cancer and HIV. In this review, current progress in the development of molecular scaffolds designed for the disruption of protein-protein interactions will be discussed with an emphasis on those active against biological targets.

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Section: Peptidomimetic -Strand Mimetic Scaffoldsmentioning

confidence: 99%

Scaffolds for Blocking Protein-Protein Interactions

Hershberger¹,

Lee²,

Chmielewski

2007

CTMC

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“…Z‐VL‐CHO was synthesized from Z‐Val‐OH and L‐leucinol as described (Levy et al, 1996). NMR, TLC, and mass spectroscopy analysis confirmed the structure and purity of the dipeptidyl aldehyde.…”

Section: Synthesis Of Z‐vl‐chomentioning

confidence: 99%

Distinct Secretases, a Cysteine Protease and a Serine Protease, Generate the C Termini of Amyloid β‐Proteins Aβ_1‐40 and Aβ_1‐42, Respectively

Figueiredo‐Pereira

Efthimiopoulos

Tezapsidis

et al. 1999

Journal of Neurochemistry

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Abstract:The carboxy-terminal ends of the 40-and 42-amino acids amyloid ␤-protein (A␤) may be generated by the action of at least two different proteases termed ␥(40)-and ␥(42)-secretase, respectively. To examine the cleavage specificity of the two proteases, we treated amyloid precursor protein (APP)-transfected cell cultures with several dipeptidyl aldehydes including N-benzyloxycarbonyl-Leu-leucinal (Z-LL-CHO) and the newly synthesized N-benzyloxycarbonyl-Val-leucinal (Z-VL-CHO). All dipeptidyl aldehydes tested inhibited production of both A␤ 1-40 and A␤ . Changes in the P 1 and P 2 residues of these aldehydes, however, indicated that the amino acids occupying these positions are important for the efficient inhibition of ␥-secretases. Peptidyl aldehydes inhibit both cysteine and serine proteases, suggesting that the two ␥-secretases belong to one of these mechanistic classes. To differentiate between the two classes of proteases, we treated our cultures with the specific cysteine protease inhibitor E-64d. This agent inhibited production of secreted A␤ 1-40 , with a concomitant accumulation of its cellular precursor indicating that ␥(40)-secretase is a cysteine protease. In contrast, this treatment increased production of secreted A␤ . No inhibition of A␤ production was observed with the potent calpain inhibitor I (acetyl-Leu-Leu-norleucinal), suggesting that calpain is not involved. Together, these results indicate that ␥(40)-secretase is a cysteine protease distinct from calpain, whereas ␥(42)-secretase may be a serine protease. In addition, the two secretases may compete for the same substrate. Dipeptidyl aldehyde treatment of cultures transfected with APP carrying the Swedish mutation resulted in the accumulation of the ␤-secretase C-terminal APP fragment and a decrease of the ␣-secretase C-terminal APP fragment, indicating that this mutation shifts APP cleavage from the ␣-secretase site to the ␤-secretase site. Key Words: Alzheimer's disease-Amyloid precursor protein-Amyloid peptide-Proteolysis-Protease inhibitors-␥-Secretase. J. Neurochem. 72, 1417-1422 (1999).Alzheimer's disease is a neurodegenerative disorder characterized by the presence of insoluble protein aggregates that accumulate in pathological lesions, such as neuritic amyloid plaques, cerebrovascular amyloid, and neurofibrillary tangles. The amyloid fibers of the neuritic amyloid plaque cores and cerebrovascular amyloid consist mainly of the 40 -42-amino acids amyloid ␤-protein (A␤), derived from the proteolytic processing of the amyloid precursor protein (APP) (for review, see Robakis, 1994). APP is a transmembrane glycoprotein processed through amyloidogenic and nonamyloidogenic pathways. In a nonamyloidogenic pathway, cleavage by ␣-secretase between A␤ sequence Lys 16 and Leu 17 of APP (Anderson et al., 1991) results in the production of an 8-kDa C-terminal APP fragment that is considered the precursor of the p3 peptides (Higaki et al., 1995;Citron et al., 1996). In the amyloidogenic pathway, proteolytic cleavage by ␤-secretase at the N t...

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“…We have previously reported the synthesis of highly potent and selective low-molecular weight (<600) thrombin inhibitors (12,13). The highest ratio of activities of human thrombin to bovine trypsin reported to date (>25000 for CVS1695, Figure 1) was achieved through excellent subnanomolar potency against thrombin and poor binding affinity for trypsin (Table 1).…”

mentioning

confidence: 99%

Highly Selective Mechanism-Based Thrombin Inhibitors: Structures of Thrombin and Trypsin Inhibited with Rigid Peptidyl Aldehydes

Krishnan¹,

Zhang²,

Håkansson³

et al. 1998

Biochemistry

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The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined and refined to R values 0.152-0. 170 at 1.8-2.1 A resolution. Since the selectivity of two of the inhibitors was >1600 with respect to trypsin, the structures of trypsin-inhibited complexes of these inhibitors were also determined (R = 0.142-0.157 at 1.9-2.1 A resolution). The selectivity appears to reside in the inability of a benzenesulfonamide group to bind at the equivalent of the D-enantiomorphic S3 site of thrombin, which may be related to the lack of a 60-insertion loop in trypsin. All the inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. Differences in the binding constants of these inhibitors are correlated with their interactions with thrombin and trypsin. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism. The structures of both thrombin and trypsin complexes show similar well-defined transition states in the S1 site and at the electrophilic carbon atom and Ser195OG. The trypsin structures, however, suggest that the first step in a two-step kinetic mechanism may involve formation of a weak transition-state complex, rather than binding dominated by the P2-P4 positions.

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Potent and Selective Thrombin Inhibitors Incorporating the Constrained Arginine Mimic l-3-Piperidyl(N-guanidino)alanine at P₁

Cited by 33 publications

References 17 publications

Scaffolds for Blocking Protein-Protein Interactions

Scaffolds for Blocking Protein-Protein Interactions

Distinct Secretases, a Cysteine Protease and a Serine Protease, Generate the C Termini of Amyloid β‐Proteins Aβ_1‐40 and Aβ_1‐42, Respectively

Highly Selective Mechanism-Based Thrombin Inhibitors: Structures of Thrombin and Trypsin Inhibited with Rigid Peptidyl Aldehydes

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Potent and Selective Thrombin Inhibitors Incorporating the Constrained Arginine Mimic l-3-Piperidyl(N-guanidino)alanine at P1

Cited by 33 publications

References 17 publications

Scaffolds for Blocking Protein-Protein Interactions

Scaffolds for Blocking Protein-Protein Interactions

Distinct Secretases, a Cysteine Protease and a Serine Protease, Generate the C Termini of Amyloid β‐Proteins Aβ1‐40 and Aβ1‐42, Respectively

Highly Selective Mechanism-Based Thrombin Inhibitors: Structures of Thrombin and Trypsin Inhibited with Rigid Peptidyl Aldehydes

Contact Info

Product

Resources

About

Potent and Selective Thrombin Inhibitors Incorporating the Constrained Arginine Mimic l-3-Piperidyl(N-guanidino)alanine at P₁

Distinct Secretases, a Cysteine Protease and a Serine Protease, Generate the C Termini of Amyloid β‐Proteins Aβ_1‐40 and Aβ_1‐42, Respectively