Pepstatin Inhibition Mechanism

Marciniszyn, Joseph P.; Hartsuck, Jean A.; Tang, Jordan

doi:10.1007/978-1-4757-0719-9_12

Cited by 41 publications

(40 citation statements)

References 18 publications

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“…In contrast, the naturally occurring peptide isovaleryl-pepstatin, which contains a central statine moiety as the transition state analogue occupying the P 1 -P 1 Ј positions in the acylated pentapeptide (35), showed subnanomolar potency as an inhibitor of recombinant cyprosin (inhibitor 1 in Table II). Whereas this response might perhaps have been expected as typical of an aspartic proteinase (30), a completely distinct acylated pentapeptide (inhibitor 2; Table II) was almost as effective as an inhibitor of cyprosin, despite having only the central statine residue in common with the sequence of isovaleryl pepstatin.…”

Section: Fig 4 Schematic Representation Of Processing Events In Pmentioning

confidence: 98%

Processing, Activity, and Inhibition of Recombinant Cyprosin, an Aspartic Proteinase from Cardoon (Cynara cardunculus)

White

Cordeiro²,

Arnold

et al. 1999

Journal of Biological Chemistry

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The cDNA encoding the precursor of an aspartic proteinase from the flowers of the cardoon, Cynara cardunculus, was expressed in Pichia pastoris, and the recombinant, mature cyprosin that accumulated in the culture medium was purified and characterized. The resultant mixture of microheterogeneous forms was shown to consist of glycosylated heavy chains (34 or 32 kDa) plus associated light chains with molecular weights in the region of 14,000 -18,000, resulting from excision of most, but not all, of the 104 residues contributed by the unique region known as the plant specific insert. SDS-polyacrylamide gel electrophoresis under non-reducing conditions indicated that disulfide bonding held the heavy and light chains together in the heterodimeric enzyme forms. In contrast, when a construct was expressed in which the nucleotides encoding the 104 residues of the plant specific insert were deleted, the inactive, unprocessed precursor form (procyprosin) accumulated, indicating that the plant-specific insert has a role in ensuring that the nascent polypeptide is folded properly and rendered capable of being activated to generate mature, active proteinase. Kinetic parameters were derived for the hydrolysis of a synthetic peptide substrate by wildtype, recombinant cyprosin at a variety of pH and temperature values and the subsite requirements of the enzyme were mapped using a systematic series of synthetic inhibitors. The significance is discussed of the susceptibility of cyprosin to inhibitors of human immunodeficiency virus proteinase and particularly of renin, some of which were found to have subnanomolar potencies against the plant enzyme.

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Section: Fig 4 Schematic Representation Of Processing Events In Pmentioning

confidence: 98%

Processing, Activity, and Inhibition of Recombinant Cyprosin, an Aspartic Proteinase from Cardoon (Cynara cardunculus)

White

Cordeiro²,

Arnold

et al. 1999

Journal of Biological Chemistry

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“…This transformation causes the geometry at the centre to change from sp 2 to sp 3 [205]. Established inhibitors, consist of part molecules, that mimic a crucial stretch of the protease recognition site and most importantly provide a sequence that duplicates the transition centre sterically without including a cleavable bond [206].…”

Section: Hiv Protease Inhibitorsmentioning

confidence: 99%

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

Kitson¹

2017

J Diagn Imaging Ther

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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 ...

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“…Pepstatin (101), which contains the unusual amino acid statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, and is proposed to be a transition state analog (63), universally inhibits the members of the aspartic proteinase family, evidence that supports the view that these enzymes all have a similar mechanism of action.…”

Section: Inhibitor Binding Studiesmentioning

confidence: 99%

Structure and Function of the Aspartic Proteinases

Dunn¹

1991

Advances in Experimental Medicine and Biology

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Pepstatin Inhibition Mechanism

Cited by 41 publications

References 18 publications

Processing, Activity, and Inhibition of Recombinant Cyprosin, an Aspartic Proteinase from Cardoon (Cynara cardunculus)

Processing, Activity, and Inhibition of Recombinant Cyprosin, an Aspartic Proteinase from Cardoon (Cynara cardunculus)

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

Structure and Function of the Aspartic Proteinases

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