Peptide Synthesis Catalyzed by an Antibody Containing a Binding Site for Variable Amino Acids

Hirschmann, Ralph; Smith, Amos B.; Taylor, Craig; Benkovic, Patricia A.; Taylor, Scott D.; Yager, Kraig M.; Sprengeler, Paul A.; Benkovic, Stephen J.

doi:10.1126/science.8023141

Cited by 363 publications

(126 citation statements)

References 21 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…Phosphonic acids are doubly-ionized at physiological pH and may affect their potency as enzymes inhibitors. These compounds exhibit interesting and useful properties such as peptide analogues [262], antiviral agents [263] and haptens for the generation of catalytic antibodies [264]. This moiety is present in potent antibiotics [265], herbicides and pesticides [266].…”

Section: α-Amino Phosphonic Acidsmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

View full text Add to dashboard Cite

Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

show abstract

Section: α-Amino Phosphonic Acidsmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

View full text Add to dashboard Cite

show abstract

“…13.1), reveal diverse and interesting biological and biochemical properties: antibacterial agents, 3 enzyme inhibitors, 4 haptens for catalytic antibodies, 5 or anti-HIV (human immunodeficiency virus) agents. 6 This chapter will focus on the asymmetric synthesis of a-substituted b-amino phosphonic (R 3 ¼ OR) and a-substituted b-amino phosphinic acids (R 3 ¼ H, R) and their derivatives 2.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of α-Substituted-β-Amino Phosphonates and Phosphinates and β-Amino Sulfur Analogs

Palacios¹,

Alonso²,

Santos³

2005

Enantioselective Synthesis of Β-Amino Acids

View full text Add to dashboard Cite

“…We reported the synthesis of hapten 1a (Fig. 1), designed to induce the formation of antibodies capable of catalyzing the formation of dipeptides of the general structure acetyl-XXX-D-Trp⅐NH 2, wherein XXX represents hydrophobic L-amino acids typified by L-Phe (1). This endeavor generated antibody 16G3, which gave rate enhancements on the order of 2 ϫ 10 4 over the background reaction with pleasingly high turnover rates (Ϸ2 min Ϫ1 ).…”

Section: The Design Of Hapten 1a: Novel Chemistry and The Generation Ofmentioning

confidence: 99%

“…S everal years ago, we undertook the generation of antibodies to catalyze peptide bond formation in part because manmade catalysts of peptide bond formation had not been described (1). We were also intrigued by the contrast between medicinal chemistry and antibody design.…”

mentioning

confidence: 99%

Cyclic peptide formation catalyzed by an antibody ligase

Smithrud¹,

Benkovic²,

Benkovic³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Cyclic hexapeptides represent a class of compounds with important, diverse biological activities. We report herein that the antibody 16G3 catalyzes the cyclization of D-Trp-Gly-Pal-Pro-Gly-Phe⅐p-nitrophenyl ester (8a) to give c-(D-Trp-Gly-Pal-Pro-Gly-L-Phe) (11a). The antibody does not, however, catalyze either epimerization or hydrolysis. The resulting rate enhancement of the cyclization by 16G3 (22-fold) was sufficient to form the desired product in greater than 90% yield. In absolute rate terms, the turnover of 16G3 is estimated to be 2 min ؊1 . The background rate of epimerization of 8a was reduced from 10 to 1% and hydrolysis from 50 to 4% in the presence of 16G3. As expected, the catalytic effects of 16G3 were blocked by the addition of an amount of the hapten equal to twice the antibody concentration. We also synthesized three diaste- S everal years ago, we undertook the generation of antibodies to catalyze peptide bond formation in part because manmade catalysts of peptide bond formation had not been described (1). We were also intrigued by the contrast between medicinal chemistry and antibody design. Generally, the former seeks by design or screening to discover small molecules that interact with macromolecules such as enzymes or receptors leading to enzyme inhibitors or to hormone͞neurotransmitter agonists͞antagonists. In contrast, catalytic antibody research involves the synthesis of haptens, designed to generate novel macromolecules (antibodies), which in turn are capable of catalyzing predetermined chemical reactions. The Design of Hapten 1a: Novel Chemistry and the Generation ofAntibody 16G3 for Bimolecular Peptide Bond Formation. We reported the synthesis of hapten 1a (Fig. 1), designed to induce the formation of antibodies capable of catalyzing the formation of dipeptides of the general structure acetyl-XXX-D-Trp⅐NH 2, wherein XXX represents hydrophobic L-amino acids typified by L-Phe (1). This endeavor generated antibody 16G3, which gave rate enhancements on the order of 2 ϫ 10 4 over the background reaction with pleasingly high turnover rates (Ϸ2 min Ϫ1 ). Our study of the kinetics implicated a sequential mechanism with no preferred order of substrate binding and no evidence for acylation of the antibody by the ester before peptide bond formation. Antibody 16G3 did not, however, catalyze either the hydrolysis or racemization of the active ester. The generation of antibodies that catalyze nonsolvolytic bimolecular bond formation is a greater challenge than the production of antibodies designed to catalyze solvolysis because an important requirement for the former is to prevent hydrolysis. The acylating agents employed in these coupling reactions were the p-nitrophenyl esters of acetyl-XXX. Although the hapten had been designed to generate antibodies that can catalyze the formation only of dipeptides, we subsequently found that antibody 16G3 also catalyzes the coupling of the p-nitrophenyl ester of N-acetyl-LPhe with D-Trp-Gly⅐NH 2 and the p-nitrophenyl ester of N-acetylGly-L-Phe with D-Trp-Gly⅐N...

show abstract

Peptide Synthesis Catalyzed by an Antibody Containing a Binding Site for Variable Amino Acids

Cited by 363 publications

References 21 publications

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Asymmetric Synthesis of α-Substituted-β-Amino Phosphonates and Phosphinates and β-Amino Sulfur Analogs

Cyclic peptide formation catalyzed by an antibody ligase

Contact Info

Product

Resources

About