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Boramino acid as a marker for amino acid transporters.

Liu Z, Chen H, Chen K, Shao Y, Kiesewetter DO, Niu G, Chen X - Sci Adv (2015)

Bottom Line: Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases.The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-).Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

ABSTRACT
Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics-boramino acids (BAAs)-that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-). Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

No MeSH data available.


Related in: MedlinePlus

Computation studies show similarities between Phe-BF3 and Phe in interaction with LAT-1 transporter.(A) Molecular electrostatic potential (MEP) prediction of Phe and its mimics. As shown, Phe-BF3 has a more nearly identical charge distribution pattern to natural Phe than the other AA mimics, such as Phe-B(OH)2 (blue indicates the distribution of positive charge, and red indicates the distribution of negative charge). (B) Predicted structure of the LAT-1/Phe-BF3 complex. LAT-1 (gray) is in solid ribbon representation. Phe-BF3 and the LAT-1 residues in the binding site are in stick representation. Hydrogen bonds between Phe-BF3 and LAT-1 (involving residues Leu87, Val97, Ala98, and Leu99) are shown as dotted green lines, which are conserved with the interaction between Phe and LAT-1 (fig. S3). (C) Summary of the predicted binding free energy (ΔGbinding), inhibition constant (Ki, T = 298.15 K), and the root mean square deviation (RMSD). These values are calculated on the basis of the best docking conformation of LAT-1 in complex with Phe and Phe-BF3.
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Figure 2: Computation studies show similarities between Phe-BF3 and Phe in interaction with LAT-1 transporter.(A) Molecular electrostatic potential (MEP) prediction of Phe and its mimics. As shown, Phe-BF3 has a more nearly identical charge distribution pattern to natural Phe than the other AA mimics, such as Phe-B(OH)2 (blue indicates the distribution of positive charge, and red indicates the distribution of negative charge). (B) Predicted structure of the LAT-1/Phe-BF3 complex. LAT-1 (gray) is in solid ribbon representation. Phe-BF3 and the LAT-1 residues in the binding site are in stick representation. Hydrogen bonds between Phe-BF3 and LAT-1 (involving residues Leu87, Val97, Ala98, and Leu99) are shown as dotted green lines, which are conserved with the interaction between Phe and LAT-1 (fig. S3). (C) Summary of the predicted binding free energy (ΔGbinding), inhibition constant (Ki, T = 298.15 K), and the root mean square deviation (RMSD). These values are calculated on the basis of the best docking conformation of LAT-1 in complex with Phe and Phe-BF3.

Mentions: Inspired by the uptake mechanism of 18F-FDG, which is an 18F-derived glucose derivative, we reasoned that a good marker of AA transportation could be derived from AA mimics. A number of mimicking strategies have been tried since the 1980s to develop AAT-inhibiting drugs. Among them, substituting carboxylate (-COO−) by boronic acid [-B(OH)2] has been the most successful because of its partial structural similarity to carboxylate (-COO−) (23). However, this strategy is not optimal; -B(OH)2 is a neutral moiety, whereas carboxylate has one negative charge. Herein, we proposed to apply the negatively charged trifluoroborate to take the position of carboxylate. Encouragingly, this proposal was greatly supported by a density functional theory (DFT) structure prediction of natural AAs and their mimics (Fig. 2A). As shown, the charge distribution of Phe-B(OH)2 is visibly different from that of natural Phe, whereas Phe-BF3 exhibits nearly identical charge distribution with natural Phe. This electrostatic similarity between carboxylate and trifluoroborate was heretofore unrealized and should be applicable to other BAAs.


Boramino acid as a marker for amino acid transporters.

Liu Z, Chen H, Chen K, Shao Y, Kiesewetter DO, Niu G, Chen X - Sci Adv (2015)

Computation studies show similarities between Phe-BF3 and Phe in interaction with LAT-1 transporter.(A) Molecular electrostatic potential (MEP) prediction of Phe and its mimics. As shown, Phe-BF3 has a more nearly identical charge distribution pattern to natural Phe than the other AA mimics, such as Phe-B(OH)2 (blue indicates the distribution of positive charge, and red indicates the distribution of negative charge). (B) Predicted structure of the LAT-1/Phe-BF3 complex. LAT-1 (gray) is in solid ribbon representation. Phe-BF3 and the LAT-1 residues in the binding site are in stick representation. Hydrogen bonds between Phe-BF3 and LAT-1 (involving residues Leu87, Val97, Ala98, and Leu99) are shown as dotted green lines, which are conserved with the interaction between Phe and LAT-1 (fig. S3). (C) Summary of the predicted binding free energy (ΔGbinding), inhibition constant (Ki, T = 298.15 K), and the root mean square deviation (RMSD). These values are calculated on the basis of the best docking conformation of LAT-1 in complex with Phe and Phe-BF3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643766&req=5

Figure 2: Computation studies show similarities between Phe-BF3 and Phe in interaction with LAT-1 transporter.(A) Molecular electrostatic potential (MEP) prediction of Phe and its mimics. As shown, Phe-BF3 has a more nearly identical charge distribution pattern to natural Phe than the other AA mimics, such as Phe-B(OH)2 (blue indicates the distribution of positive charge, and red indicates the distribution of negative charge). (B) Predicted structure of the LAT-1/Phe-BF3 complex. LAT-1 (gray) is in solid ribbon representation. Phe-BF3 and the LAT-1 residues in the binding site are in stick representation. Hydrogen bonds between Phe-BF3 and LAT-1 (involving residues Leu87, Val97, Ala98, and Leu99) are shown as dotted green lines, which are conserved with the interaction between Phe and LAT-1 (fig. S3). (C) Summary of the predicted binding free energy (ΔGbinding), inhibition constant (Ki, T = 298.15 K), and the root mean square deviation (RMSD). These values are calculated on the basis of the best docking conformation of LAT-1 in complex with Phe and Phe-BF3.
Mentions: Inspired by the uptake mechanism of 18F-FDG, which is an 18F-derived glucose derivative, we reasoned that a good marker of AA transportation could be derived from AA mimics. A number of mimicking strategies have been tried since the 1980s to develop AAT-inhibiting drugs. Among them, substituting carboxylate (-COO−) by boronic acid [-B(OH)2] has been the most successful because of its partial structural similarity to carboxylate (-COO−) (23). However, this strategy is not optimal; -B(OH)2 is a neutral moiety, whereas carboxylate has one negative charge. Herein, we proposed to apply the negatively charged trifluoroborate to take the position of carboxylate. Encouragingly, this proposal was greatly supported by a density functional theory (DFT) structure prediction of natural AAs and their mimics (Fig. 2A). As shown, the charge distribution of Phe-B(OH)2 is visibly different from that of natural Phe, whereas Phe-BF3 exhibits nearly identical charge distribution with natural Phe. This electrostatic similarity between carboxylate and trifluoroborate was heretofore unrealized and should be applicable to other BAAs.

Bottom Line: Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases.The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-).Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

ABSTRACT
Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics-boramino acids (BAAs)-that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-). Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

No MeSH data available.


Related in: MedlinePlus