<scp>D</scp>‐Tyrosine as a Chiral Precusor to Potent Inhibitors of Human Nonpancreatic Secretory Phospholipase A<sub>2</sub> (IIa) with Antiinflammatory Activity

Hansford, Karl A.; Reid, Robert C.; Clark, Christopher I.; Tyndall, Joel D. A.; Whitehouse, M. W.; Guthrie, Tom; McGeary, Ross P.; Schäfer, Karl; Martin, Jennifer L.; Fairlie, David P.

doi:10.1002/cbic.200390029

Cited by 78 publications

(105 citation statements)

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“…The target specificity of any drug in vivo can never be completely certain, but there is considerable evidence that KH064 is a highly target-selective drug. We have reported its crystal structure (pdb code: 1kq) in complex with sPLA 2 -IIA (27), and identified its specific interactions within the unusual active site of that enzyme. In vitro radioligand binding and fluorometric/calorimetric functional assays (D.P.…”

Section: Discussionmentioning

confidence: 99%

“…This dose was chosen because it was effective in the rat models described above (27)(28)(29). Olive oil-treated SHR and WKY rats served as vehicle controls.…”

Section: Shr and Wistar-kyoto (Wky) Ratsmentioning

confidence: 99%

“…The present study has investigated whether the sPLA 2 -IIA inhibitor 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid (designated here as KH064 but referred to as compound "2b" in Ref. 27) prevents cardiovascular remodeling in young male SHR during the development of hypertension. KH064 is an orally active, competitive and reversible inhibitor with high potency (IC 50 29 nM) and selectivity (sPLA 2 -V: IC 50 Ͼ 5 M) for the human sPLA 2 -IIA enzyme (27,28).…”

mentioning

confidence: 99%

“…27) prevents cardiovascular remodeling in young male SHR during the development of hypertension. KH064 is an orally active, competitive and reversible inhibitor with high potency (IC 50 29 nM) and selectivity (sPLA 2 -V: IC 50 Ͼ 5 M) for the human sPLA 2 -IIA enzyme (27,28). This inhibitor was effective at 5 mg/kg/day p.o.…”

mentioning

confidence: 99%

“…This inhibitor was effective at 5 mg/kg/day p.o. as an anti-inflammatory drug in rat models of adjuvant-induced arthritis (27), intestinal ischemia-reperfusion injury (28), and inflammatory bowel disease (29). KH064 also reduces NOx production from the myocardium, myocardial damage, and cardiomyocyte death during cold ischemia associated with donor heart preservation, and sPLA 2 activation has been implicated in up-regulation of NO synthase-2 during cardiac ischemia (25).…”

mentioning

confidence: 99%

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Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Levick¹,

Loch²,

Rolfe³

et al. 2006

The Journal of Immunology

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The development of fibrosis in the chronically hypertensive heart is associated with infiltration of inflammatory cells and cardiac hypertrophy. In this study, an inhibitor of the proinflammatory enzyme, group IIA human secretory phospholipase A2 (sPLA2-IIA), has been found to prevent collagen deposition as an important component of cardiovascular remodeling in a rat model of developing chronic hypertension. Daily treatment of young male spontaneously hypertensive rats (SHR) with an sPLA2-IIA inhibitor (KH064, 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid, 5 mg/kg/day p.o.) prevented increases in the content of perivascular (SHR 20.6 ± 0.9%, n = 5; SHR+KH064 14.0 ± 1.2%, n = 5) and interstitial (SHR 7.9 ± 0.3%, n = 6; SHR+KH064 5.4 ± 0.7%, n = 6) collagen in the left ventricle of rat hearts, but did not affect numbers of infiltrating monocytes/macrophages, left ventricular hypertrophy (SHR 2.88 ± 0.08, n = 12; SHR+KH064 3.09 ± 0.08 mg/g body weight, n = 9), increased systolic blood pressure, or thoracic aortic responses. This selective antifibrotic activity suggests that sPLA2-IIA may have an important but specific role in cardiac fibrosis, and that its inhibitors could be useful in dissecting molecular pathways leading to fibrotic conditions.

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Section: Discussionmentioning

confidence: 99%

“…This dose was chosen because it was effective in the rat models described above (27)(28)(29). Olive oil-treated SHR and WKY rats served as vehicle controls.…”

Section: Shr and Wistar-kyoto (Wky) Ratsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Levick¹,

Loch²,

Rolfe³

et al. 2006

The Journal of Immunology

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The Binding Mode of Petrosaspongiolide M to the Human Group IIA Phospholipase A₂: Exploring the Role of Covalent and Noncovalent Interactions in the Inhibition Process

Monti¹,

Casapullo²,

Cavasotto³

et al. 2009

Chemistry A European J

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We report an analysis of the mechanism of human group IIA secretory phospholipase A(2) (sPLA(2)-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a gamma-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA(2)-IIA Lys67 residue, located near the enzyme-membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of sPLA(2)-IIA through several van der Waals/electrostatic complementarities. The two events cannot co-occur on a single PLA(2) molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA(2) supramolecular complexes. These insights could suggest new PLA(2)-inhibition-based therapeutic strategies.

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Differential expression of sPLA₂ following spinal cord injury and a functional role for sPLA₂‐IIA in mediating oligodendrocyte death

Titsworth

Cheng

et al. 2009

Glia

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After the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipases activity and cytosolic PLA2-IVα protein expression increased. However, the expression of secreted isoforms of PLA2 (sPLA2) and their possible roles in oligodendrocyte death following SCI remains unclear. Here we report that mRNAs extracted 15 min, 4 hr, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA2-IIA and IIE at 4 hr after injury. In contrast, SCI induced down regulation of sPLA2-X, and no change in sPLA2-IB, IIC, V, and XIIA expression. At the lesion site, sPLA2-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA2-IIA (0.01, 0.1, or 2 μM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA2-IIA inhibitor, before a 30 min H2O2 injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 hr. Similarly, pretreatment with S3319 before injury with IL-1β and TNFα prevented cell death and loss of oligodendrocyte processes at 72 hr. Collectively, these findings suggest that sPLA2-IIA and IIE are increased following SCI, that increased sPLA2-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA2 can create sparing of oligodendrocytes in two distinct injury models. Therefore sPLA2-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI.

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D‐Tyrosine as a Chiral Precusor to Potent Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂ (IIa) with Antiinflammatory Activity

Cited by 78 publications

References 40 publications

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

The Binding Mode of Petrosaspongiolide M to the Human Group IIA Phospholipase A₂: Exploring the Role of Covalent and Noncovalent Interactions in the Inhibition Process

Differential expression of sPLA₂ following spinal cord injury and a functional role for sPLA₂‐IIA in mediating oligodendrocyte death

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D‐Tyrosine as a Chiral Precusor to Potent Inhibitors of Human Nonpancreatic Secretory Phospholipase A2 (IIa) with Antiinflammatory Activity

Cited by 78 publications

References 40 publications

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

The Binding Mode of Petrosaspongiolide M to the Human Group IIA Phospholipase A2: Exploring the Role of Covalent and Noncovalent Interactions in the Inhibition Process

Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2‐IIA in mediating oligodendrocyte death

Contact Info

Product

Resources

About

D‐Tyrosine as a Chiral Precusor to Potent Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂ (IIa) with Antiinflammatory Activity

The Binding Mode of Petrosaspongiolide M to the Human Group IIA Phospholipase A₂: Exploring the Role of Covalent and Noncovalent Interactions in the Inhibition Process

Differential expression of sPLA₂ following spinal cord injury and a functional role for sPLA₂‐IIA in mediating oligodendrocyte death