Poly(ADP-ribose) polymerase inhibitors

Garry J. Southan, Csaba Szabo

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.

Original languageEnglish (US)
Pages (from-to)321-340
Number of pages20
JournalCurrent Medicinal Chemistry
Volume10
Issue number4
StatePublished - 2003
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Pharmacology
Medical problems
NAD
Adenosine Diphosphate
Traumatic Shock
Adenosine Diphosphate Ribose
Nervous System Trauma
Signal transduction
DNA Breaks
Oxidative stress
Autoimmune Experimental Encephalomyelitis
DNA
Neurology
Enzymes
Colitis
Nuclear Proteins
Antineoplastic Agents
Histones
DNA Damage

Keywords

  • Aminobenzamide
  • Apoptosis
  • Arthritis
  • Colitis
  • Diabetes
  • DNA repair
  • Inflammation
  • Myocardial ischemia
  • Necrosis
  • Nicotinamide
  • Nitric oxide
  • Peroxynitrite
  • Poly(ADB-ribose) polymerase
  • Reperfusion
  • Stroke
  • Uveitis

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Poly(ADP-ribose) polymerase inhibitors. / Southan, Garry J.; Szabo, Csaba.

In: Current Medicinal Chemistry, Vol. 10, No. 4, 2003, p. 321-340.

Research output: Contribution to journalArticle

Southan, GJ & Szabo, C 2003, 'Poly(ADP-ribose) polymerase inhibitors', Current Medicinal Chemistry, vol. 10, no. 4, pp. 321-340.
Southan, Garry J. ; Szabo, Csaba. / Poly(ADP-ribose) polymerase inhibitors. In: Current Medicinal Chemistry. 2003 ; Vol. 10, No. 4. pp. 321-340.
@article{6380ab3464d04df5b1c47b5232fd1d34,
title = "Poly(ADP-ribose) polymerase inhibitors",
abstract = "Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.",
keywords = "Aminobenzamide, Apoptosis, Arthritis, Colitis, Diabetes, DNA repair, Inflammation, Myocardial ischemia, Necrosis, Nicotinamide, Nitric oxide, Peroxynitrite, Poly(ADB-ribose) polymerase, Reperfusion, Stroke, Uveitis",
author = "Southan, {Garry J.} and Csaba Szabo",
year = "2003",
language = "English (US)",
volume = "10",
pages = "321--340",
journal = "Current Medicinal Chemistry",
issn = "0929-8673",
publisher = "Bentham Science Publishers B.V.",
number = "4",

}

TY - JOUR

T1 - Poly(ADP-ribose) polymerase inhibitors

AU - Southan, Garry J.

AU - Szabo, Csaba

PY - 2003

Y1 - 2003

N2 - Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.

AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD+ and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.

KW - Aminobenzamide

KW - Apoptosis

KW - Arthritis

KW - Colitis

KW - Diabetes

KW - DNA repair

KW - Inflammation

KW - Myocardial ischemia

KW - Necrosis

KW - Nicotinamide

KW - Nitric oxide

KW - Peroxynitrite

KW - Poly(ADB-ribose) polymerase

KW - Reperfusion

KW - Stroke

KW - Uveitis

UR - http://www.scopus.com/inward/record.url?scp=0037239590&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037239590&partnerID=8YFLogxK

M3 - Article

C2 - 12570705

AN - SCOPUS:0037239590

VL - 10

SP - 321

EP - 340

JO - Current Medicinal Chemistry

JF - Current Medicinal Chemistry

SN - 0929-8673

IS - 4

ER -