Design and synthesis of inhibitors incorporating ?-amino acids of metalloendopeptidase EC 3.4.24.15

Steer, David; Lew, Rebecca A.; Perlmutter, Patrick; Smith, A. Ian; Aguilar, Mibel

doi:10.1002/1099-1387(200009)6:9<470::aid-psc287>3.0.co;2-x

Cited by 27 publications

(18 citation statements)

References 17 publications

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“…They are degradable by proteolysis. Because β‐amino acids are nonproteinogenic, β‐amino acid‐containing peptides are better choice for drug design for their better stability against proteolytic degradation …”

Section: Introductionmentioning

confidence: 99%

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Kumar¹,

Paul

Kalita

et al. 2016

Chem Biol Drug Des

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Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β-sheet breaker α/β-hybrid peptide (BSBHp) and the underlying mechanisms against Aβ -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with the peptide Aβ to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca , and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ -induced toxicity by retaining cell viability, suppressing generation of ROS, Ca levels, and effectively protects neuronal apoptosis by suppressing pro-apoptotic protein Bax and up-regulating antiapoptotic protein Bcl-2. These results suggest that α/β-hybrid peptide has neuroprotective effects against Aβ -induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Kumar¹,

Paul

Kalita

et al. 2016

Chem Biol Drug Des

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“…84 (2001) 3508 7 ) Indeed, a simple molecular-mechanics conformational search of the a/b 3 -dipeptide Ac-(R)-Ala-(S)-b 3 -HAla-NMe on the basis of the MMFF 94 force field predicts that nine-and eleven-membered H-bonded rings are among the lowest-energy conformers. 8 ) Since Abderhalden [21], the incorporation of b-amino acids into a-peptides was tested as a means of increasing proteolytic stability and of modifying structural and pharmacological properties [22]. 9 ) Recently, Gellman and co-workers [23] have used cyclic b-amino acid residues to construct an otherwise apeptidic haripin turn.…”

mentioning

confidence: 99%

Linear, Peptidase-Resistantβ2/β3-Di- andα/β3-Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor, Preliminary Communication

Seebàch¹,

Rueping²,

Arvidsson³

et al. 2001

HCA

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Nervous System Research, S-386-745, Novartis Pharma AG, CH-4002 Basel N-Acyl-b 2 /b 3 -dipeptide-amide somatostatin analogs, 5 ± 8, with b 2 -HTrp-b 3 -HLys (×natural× sequence) and b 2 -HLys-b 3 -HTrp (retro-sequence) have been synthesized (in solution). Depending on their relative configurations and on the nature of the terminal N-acyl and terminal C-amino group, the linear b-dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to > 10000 nanomolar (Fig. 3). Also, N-Actetrapeptide amides 9 and 10, which contain one a-and three b-amino acid residues (N-b-a-b-b-C), have been prepared (solid-phase synthesis), with the natural (Phe, Trp, Lys, Thr) and the retro-sequence (Thr, Lys, Trp, Phe) of side chains and with two different configurations, each, of the two central amino acid residues. The novel −mixed×, linear a/b-peptides have affinities for the hsst 4 receptor ranging from 23 to > 10000 nanomolar (Fig. 4), and, like −pure× b-peptides, they are completely stable to a series of proteolytic enzymes. Thus, the peptidic turn of the cyclic tetradecapeptide somatostatin (Fig. 1) can be mimicked by simple linear di-and tetrapeptides. The tendency of b-dipeptides for forming hydrogen-bonded rings is confirmed by calculations at the B3LYP/6-31G(d,p) level (Fig. 2). The reported results open new avenues for the design of low-molecularweight peptidic drugs. b-Peptides have recently emerged as a promising class of peptidomimetics for medicinal chemistry. The ability of b-peptides (for reviews, see [1]) to adopt secondary structures such as helices [1], sheets [2a] [3], and, especially, turns [3] suggests that these compounds might be structural and functional mimics of natural peptides. The potential of such mimics is evident from the facts that a) these secondary structures can be readily designed [1 ± 5], and that b) the b-peptides are completely stable against proteolytic degradation in vitro and in vivo [2a] [6].So far, b-peptides, designed to form amphiphilic helices, have been shown to inhibit an intestinal membrane-bound cholesterol-and lipid-transporting protein [5]. Also, similar peptides have been shown to possess antimicrobial, and sometimes, hemolytic activities [7].

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“…In conclusion, a b-amino acid could replace an a-amino acid within the sequence of a bioactive peptide provided that the additional methylene group does not cause steric hindrance and does not confine orientations of the side chain to regions of space different from those permitted in the a-amino acid. Thus, insertion of a single b-amino acid in a bioactive peptide could be favourably applied to improve both biological potency and enzymatic stability of the original peptide, as already shown with the empiric design of a metalloendopeptidase tripeptide inhibitor [45].…”

Section: Discussionmentioning

confidence: 96%

Structural and biological effects of a β²‐ or β³‐amino acid insertion in a peptide

Sagan

Milcent

Ponsinet

et al. 2003

European Journal of Biochemistry

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Design and synthesis of inhibitors incorporating ?-amino acids of metalloendopeptidase EC 3.4.24.15

Cited by 27 publications

References 17 publications

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Linear, Peptidase-Resistantβ2/β3-Di- andα/β3-Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor, Preliminary Communication

Structural and biological effects of a β²‐ or β³‐amino acid insertion in a peptide

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Design and synthesis of inhibitors incorporating ?-amino acids of metalloendopeptidase EC 3.4.24.15

Cited by 27 publications

References 17 publications

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Linear, Peptidase-Resistantβ2/β3-Di- andα/β3-Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor, Preliminary Communication

Structural and biological effects of a β2‐ or β3‐amino acid insertion in a peptide

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Structural and biological effects of a β²‐ or β³‐amino acid insertion in a peptide