Name: Ala-Ala-Asn-PAB
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Synonyms

(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoyl]amino]-N-[4-(hydroxymethyl)phenyl]butanediamide

IUPAC Name

(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoyl]amino]-N-[4-(hydroxymethyl)phenyl]butanediamide

SMILES

CC(C(=O)NC(C)C(=O)NC(CC(=O)N)C(=O)NC1=CC=C(C=C1)CO)N

InChI

InChI=1S/C17H25N5O5/c1-9(18)15(25)20-10(2)16(26)22-13(7-14(19)24)17(27)21-12-5-3-11(8-23)4-6-12/h3-6,9-10,13,23H,7-8,18H2,1-2H3,(H2,19,24)(H,20,25)(H,21,27)(H,22,26)/t9-,10-,13-/m0/s1

InChIKey

VPXFRPRRAXTBSH-KWBADKCTSA-N

Appearance

Soild powder

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-20°C (International: -20°C)

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-20°C

Ala-Ala-Asn-PAB, a synthetic peptide utilized in diverse bioscience applications, plays a pivotal role in various fields. Here are four key applications presented with high perplexity and burstiness:

Biomarker Discovery: Serving as a substrate, Ala-Ala-Asn-PAB aids in pinpointing specific proteases implicated in disease processes. By undergoing cleavage in the presence of select proteases, it facilitates the detection of abnormal protease activity, offering insights into potential pathological conditions. This attribute makes it a valuable tool in the quest for unearthing and validating disease biomarkers, shedding light on crucial diagnostic avenues.

Drug Development: Within the realm of pharmaceutical research, Ala-Ala-Asn-PAB emerges as a cornerstone for screening and developing inhibitors or activators targeting specific proteases. Through a nuanced understanding of how diverse compounds interact with the peptide substrate, researchers can identify viable therapeutic agents, paving the way for novel treatments in diseases like cancer and Alzheimer's. This process is fundamental in the perpetual quest for groundbreaking pharmaceutical interventions.

Enzyme Kinetics: In the realm of enzymology, Ala-Ala-Asn-PAB stands out as a go-to choice for studying the kinetics of protease activity. By meticulously monitoring the hydrolysis rate of the peptide, scientists glean crucial insights into enzyme efficiency and mechanistic intricacies. This knowledge serves as a cornerstone for crafting enzyme inhibitors and unraveling the finely tuned regulatory mechanisms governing enzyme function, offering a deeper understanding of enzymatic processes.

Diagnostics: Ala-Ala-Asn-PAB finds its place in diagnostic assays as a key player in monitoring protease activity within biological samples. The cleavage of this peptide becomes a telltale sign detectable through various techniques, providing a quantitative measure of enzyme activity. This application proves especially valuable in clinical diagnostics targeting conditions where protease activity serves as a hallmark, allowing for precise and targeted diagnostic interventions.

1. A humanised mouse model of cytokine release: comparison of CD3-specific antibody fragments

S Shaw, S L Malcolm, E L Smith, T Bourne J Immunol Methods . 2012 Oct 31;384(1-2):33-42. doi: 10.1016/j.jim.2012.07.001.

CD3-specific antibodies have shown clinical efficacy in both transplantation and autoimmunity. However, targeting CD3 in this way can lead to T-cell activation and a serious cytokine release syndrome mediated by Fcγ receptor binding. An in vivo mouse model has been developed using severe combined immunodeficient (SCID) mice to detect human T-cell depletion and cytokine release into the circulation after administration of OKT3. This system has been used to evaluate OKT3 antibody fragments lacking the entire Fc region alongside whole antibody constructs. These data clearly show that cytokine release is detected with all OKT3 antibody constructs and fragments tested and these can be ranked from highest to lowest as follows: mIgG2a>hIgG1 (Ala-Ala)>hIgG1 diFab' maleimide (DFM)>hIgG1 F(ab')₂>mIgG2a F(ab')₂>hIgG1 Fab'. Furthermore, the monovalent hIgG1 Fab' fragment gives the least cytokine release but it does not deplete human T-cells in this assay format. This suggests that T-cell activation may be playing a role in the mechanism of action of anti-CD3 antibodies and consequently the unwanted cytokine release is potentially unavoidable for this class of molecules. This model system provides a useful tool to aid in understanding and reducing the potential risks of cytokine release following antibody therapy.

2. Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding

Brendan M Crowley, Dale L Boger J Am Chem Soc . 2006 Mar 8;128(9):2885-92. doi: 10.1021/ja0572912.

An effective synthesis of [Psi[CH(2)NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K(a) = 5.2 x 10(3) M(-1)) and a 35-fold reduction in affinity for D-Ala-D-Ala (K(a) = 4.8 x 10(3) M(-1)), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 microg/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to d-Ala-d-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics.

3. Does Thermal Breathing Affect Collision Cross Sections of Gas-Phase Peptide Ions? An Ab Initio Molecular Dynamics Study

Xiaosong Li, František Tureček, Robert Pepin, Matthew F Bush, Alessio Petrone, Kenneth J Laszlo J Phys Chem Lett . 2016 Jul 21;7(14):2765-71. doi: 10.1021/acs.jpclett.6b01187.

Ab initio molecular dynamics (AIMD) with density functional theory (DFT) was applied to explore conformational motions and collision cross sections (Ω) of folded (2) and extended (7) conformers of doubly charged peptide ions, (Ala-Ala-Leu-Arg + 2H)(2+), in the gas phase at 300 and 473 K. The experimental Ω of (Ala-Ala-Leu-Arg +2H)(2+) was measured as 149 ± 1.2 Å(2) at 298 K. Thermally distributed mean values of Ω for 2 and 7 at 300 and 473 K were only 0.8-1.1% larger than for the equilibrium 0 K structures. Long (>10 ps) trajectory calculations indicated entropy-driven conformational change of 2 to 7 that occurred at random within a ~ 4 ps time window. The experimental Ω was found to fit the calculated population averaged values for 2 and 7, indicating a rapid conformer interconversion. Overall, thermal breathing had only a minor effect on the peptide ion collision cross sections.