The design and synthesis of inhibitors of the cysteinyl protease, Der p I

Billson, Jeremy; Clark, Jonathan; Conway, Simon P.; Hart, Terance W.; Johnson, Tony; Langston, Steven; Ramjee, Manoj K.; Quibell, Martin; Scott, R. K.

doi:10.1016/s0960-894x(98)00151-6

Cited by 12 publications

(10 citation statements)

References 25 publications

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“…21,22 The elucidation of the 3-dimensional structure of Der p 1 now offers a basis to design and test specific inhibitors for both in vitro and in vivo experiments, and as a part of a new therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen

Halleux

Stura

VanderElst

et al. 2006

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 99%

Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen

Halleux

Stura

VanderElst

et al. 2006

Journal of Allergy and Clinical Immunology

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“…Other parasitic cysteine proteases that are possible human therapeutic targets include protease of Leishmania mexicana [157][158][159], and of Der p 1 (dust mite, causative of asthma) [160,161]. While vinyl sulfone inhibitors, such as 66 or 67, are not toxic at therapeutic doses when administered in rats or dogs, concern about their selectivity for cruzain against other human cysteine proteases, i.e., cathepsin B or cathepsin L, has been raised and is a serious issue [151,[153][154][155].…”

Section: Cruzain or Cruzipainmentioning

confidence: 99%

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Leung-Toung

Li²,

Tam³

et al. 2002

CMC

128

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Biological thiol-dependent enzymes have recently received extensive attention in the literature because of their involvement in a variety of physiopathological conditions. The active thiol groups of these enzymes are derived from the cysteine residues present. Hence, in a biological system, the selective reversible or irreversible inhibition of the activity of these enzymes by modification of the thiol moiety may potentially lead to the development of a chemotherapeutic treatment. Despite all the research efforts involved in the attempt to develop potential chemotherapeutic treatments for the major diseases involving cysteine proteases, there are in fact no such treatments available yet. However, AG7088 (1) an inhibitor of rhinovirus-3C is in phase II/III clinical trial for the treatment of common cold and VX-740 (2, pralnacasan) an inhibitor of caspase-1 is in phase II clinical trial as an anti-inflammatory agent for rheumatoid arthritis. Several other cysteine protease inhibitors (i.e., cathepsin K, and S) are in pre-clinical evaluation or pre-clinical development. Structure-based drug design approaches have been instrumental in the development of these inhibitors. Intensive biochemical studies on the cysteine proteases have shed some light on some potential targets for therapeutic development. In addition, new techniques and new ideas are constantly emerging. As such, an up-to-date review of the literature on thiol-dependent enzymes as potential targets and their inhibitors designed from peptidic, modified peptidomimetic scaffolds and from small heterocyclic molecules is presented.

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“…The design and synthesis of PTL11028 (benzoyl‐valyl‐alanyl‐norleucyl‐ (2,6‐ bistrifluoromethyl)‐benzyl‐ acyloxymethylketone) is described elsewhere [ 15]. PTL11028 was diluted to 12.5 m m in DMSO, with further dilutions being prepared to a 250 μ m stock in tissue culture media or buffer as required.…”

Section: Methodsmentioning

confidence: 99%

“…The enzymatic activity of purified Der p 1 was assessed by measuring cleavage of a peptide‐based fluorogenic substrate identified by RAPID TM technology [ 15], the substrate being 2‐aminobenzoic acid‐valyl‐alanyl‐norleucyl‐serinyl‐(3‐nitro)‐tyrosinyl‐aspartamide (ABZ‐VAnLS‐(NO 2 )Y‐D‐NH 2 ). This peptide substrate and the mode of fluorescent labelling have previously been described [ 15, 17]. Der p 1 was diluted to 1 μg/mL (40 n m ) in 50 m m potassium phosphate buffer, pH 8.25, containing 1 m m cysteine and added to a quartz cuvette (Infrasil 10 mm path length, Starna, Essex, UK).…”

Section: Methodsmentioning

confidence: 99%

“…The generation of a high affinity irreversible inhibitor of Der p 1 has been previously described [ 15]. In this paper we examine the inhibitory activity of this compound in a number of biological assay systems, including Der p 1‐mediated cleavage of CD23 from human B cells and HDM‐induced human bronchial epithelial cell permeability studies.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Functional effects of the inhibition of the cysteine protease activity of the major house dust mite allergen Der p 1 by a novel peptide‐based inhibitor

John¹,

Rusznák²,

Ramjee³

et al. 2000

Clin Experimental Allergy

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PTL11028 is a highly potent and selective irreversible inhibitor of the cysteine protease activity of Der p 1, an activity that may be modulated in vivo by some human cystatins. PTL11028 prevents the Der p 1-mediated cleavage of CD23 from human B cells and significantly reduces HDM-induced permeabilization of the epithelial barrier. PTL11028 is an important tool to examine the biological effects of Der p 1 in a range of in vitro and in vivo model systems.

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The design and synthesis of inhibitors of the cysteinyl protease, Der p I

Cited by 12 publications

References 25 publications

Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen

Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Functional effects of the inhibition of the cysteine protease activity of the major house dust mite allergen Der p 1 by a novel peptide‐based inhibitor

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