Inhibition of chymotrypsin by phosphonate and phosphonamidate peptide analogs

Bartlett, Paul A.; Lamden, Lawrence A.

doi:10.1016/0045-2068(86)90002-7

Cited by 80 publications

(42 citation statements)

References 31 publications

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“…2A; ref. 26), and found that it inhibited GlpG-catalyzed proteolysis of the TM fusion protein substrate with an apparent IC50 of around 50μM (27) (Fig. 2B, C).…”

Section: Resultsmentioning

confidence: 97%

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Conformational Change in Rhomboid Protease GlpG Induced by Inhibitor Binding to Its S′ Subsites

et al. 2012

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Rhomboid protease conducts proteolysis inside the hydrophobic environment of the membrane. The conformational flexibility of the protease is essential for the enzyme mechanism, but the nature of this flexibility is not completely understood. Here we describe the crystal structure of rhomboid protease GlpG in complex with a phosphonofluoridate inhibitor, which is covalently bonded to the catalytic serine, and extends into the S’ side of the substrate binding cleft. Inhibitor binding causes subtle but extensive changes in the membrane protease. Many transmembrane helices tilt and shift positions, and the gap between S2 and S5 is slightly widened so that the inhibitor can bind between them. The side chain of Phe-245 from a loop (L5) that acts as a cap rotates and uncovers the opening of the substrate binding cleft to the lipid bilayer. A concurrent turn of the polypeptide backbone at Phe-245 moves the rest of the cap and exposes the catalytic serine to aqueous solution. This study, together with earlier crystallographic investigation of smaller inhibitors, suggests a simple model to explain substrate binding to rhomboid protease.

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“…2A; ref. 26), and found that it inhibited GlpG-catalyzed proteolysis of the TM fusion protein substrate with an apparent IC50 of around 50μM (27) (Fig. 2B, C).…”

Section: Resultsmentioning

confidence: 97%

“…Cbz-Ala P (O- i Pr)F was prepared according to the eight step sequence previously reported by Bartlett and coworkers (26). …”

Section: Methodsmentioning

confidence: 99%

Conformational Change in Rhomboid Protease GlpG Induced by Inhibitor Binding to Its S′ Subsites

et al. 2012

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“…The choice of alanine substitution for P 1 ′ in 2 was based on its effective earlier use as a steric shield for the silanediol to minimize oligomerization. 18 Chymotrypsin is relatively insensitive toward substitution at P 1 ′ in substrates 19 and methyl substitution was effective in phosphoramide inhibitors developed by Bartlett, et al 20 Evaluation of 2 as an inhibitor used the commercially available chymotrypsin substrate 3 (vide infra). Termination with a primary amide ensures that the polarity and hydrogen bonding capabilities of the substrate are retained.…”

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confidence: 99%

Serine Protease Inhibition by a Silanediol Peptidomimetic

Singh

Sieburth

2012

Org. Lett.

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Silanediol peptidomimetics are demonstrated to inhibit a serine protease. Asymmetric synthesis of the inhibitor was accomplished using Brown hydroboration and CBS reduction of an acylsilane intermediate. The silanediol product was found to inhibit the serine protease chymotrypsin with a Ki of 107 nM. Inhibition of the enzyme may involve exchange of a silane hydroxyl with the active site serine nucleophile, contrasting with previous silanediol protease inhibitors.

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“…Generally, phosphonamidate pseudopeptides are prepared by the reactions of Nprotected phosphonochloridates with a suitable amino acid derivative or peptide fragment [282,283] or by the direct condensation of phosphonate monoesters with amino acid esters or peptide esters in the presence of coupling reagents [284,285]. In turn, phosphonochloridates are accessible by the reaction of dialkyl phosphonates with one equivalent of phosphorus pentachloride [286][287][288][289], by reaction of monoesters with thionyl chloride or oxalyl chloride [290][291][292], and by oxidative chlorination of phosphonate esters (Scheme 5.76) [293,294].…”

Section: Peptides Containing An Aminophosphinic Acid Unitmentioning

confidence: 99%

Chemistry of Aminophosphonic Acids and Phosphonopeptides

Kukhar

Romanenko

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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Aminophosphonic (and aminophosphinic) acids occupy a prominent position in the understanding of bioprocesses in living organisms and in the construction of new bioregulators -pharmaceuticals and agrochemicals. The so-called phosphorus analogs of the amino acids, aminophosphonic and aminophosphinic acids, are amino acid mimetics in which the carboxylic group is substituted by a phosphonic acid residue P(O)(OH) 2 or phosphinic acid group P(O)(OH)R. The replacement of the carboxylic group by a phosphonic or related moiety results in a number of important consequences: the central atom of a phosphonic acid function consists of an additional substituent that has a tetrahedral configuration in contrast to the planar carbonyl atom of carboxylic group. There are also significant differences in the acidity and steric bulk of these residues. The tetrahedral configuration of the pentavalent phosphorus atom mimics the transition state of the peptide bond cleavage reaction in some enzyme-substrate interactions that is used in the synthesis of new inhibitors. The hydrolytic stability of CÀP bonds is often used in order to prepare stable analogs of bioactive phosphates OÀP(O)(OH) 2 . In addition, aminophosphonic acids and their derivatives are important as metal-complexing agents, which have diagnostic and therapeutic applications, and as industrial chemicals in water treatment, metal extraction, or pollution control.Synthesis, and the chemical, physical, and biological properties of aminophosphonic acids and some directions for their practical application are presented in a number of reviews and book chapters. The most comprehensive account of the chemistry and biology of aminophosphonates and aminophosphinate which covers literature up to 2000 is presented in Kukhar and Hudson ([1] and references therein). Readers are referred to this reference for more detailed information concerning specific aspects of the chemistry and biological activity of aminophosphonic acid derivatives. The purpose of this chapter is to give an updated report on aminophosphonic acids as analogs of amino acids. Numerous heterocyclic compounds that contain both phosphonic and amino groups will not be covered in this report.

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Inhibition of chymotrypsin by phosphonate and phosphonamidate peptide analogs

Cited by 80 publications

References 31 publications

Conformational Change in Rhomboid Protease GlpG Induced by Inhibitor Binding to Its S′ Subsites

Conformational Change in Rhomboid Protease GlpG Induced by Inhibitor Binding to Its S′ Subsites

Serine Protease Inhibition by a Silanediol Peptidomimetic

Chemistry of Aminophosphonic Acids and Phosphonopeptides

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