Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors

Bozdağ, Murat; Dreker, Tobias; Henry, Christophe; Tosco, Paolo; Vallaro, Maura; Fruttero, Roberta; Scozzafava, Andrea; Carta, Fabrizio; Supuran, Claudiu T.

doi:10.1016/j.bmcl.2012.11.102

Cited by 34 publications

(27 citation statements)

References 46 publications

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“…While synthetic and biologic disease-modifying anti-inflammatory drugs remain the cornerstone of the therapy of RA, inhibitors of PADs, which are currently in the developmental pipeline [107], are of potential therapeutic utility in the prevention and/or therapy of RA.…”

Section: Anti-inflammatory/immunosuppressive Therapiesmentioning

confidence: 99%

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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Smoking is now well recognised not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. Recent studies have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smokingrelated RA. These involve release of the enzymes, peptidylarginine deiminases (PADs) 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. PADs, in turn, mediate the conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide/protein pathogenic autoantibodies (ACPA), an event which precedes the development of RA. This review is focused primarily on smoking-mediated harmful chronic inflammatory responses, both local and systemic, which promote the formation of ACPA, as well as the possible involvement of other types of outdoor and indoor pollution in the pathogenesis of RA. This is preceded by a brief overview of the evidence implicating smoking as a risk factor for development of ACPA-positive RA.Keywords: Anti-citrullinated peptide/protein antibodies; airway microbiota; atmospheric pollution; heavy metals; peptidylarginine deiminases; smoking cessation strategies. ImplicationsChronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of rheumatoid arthritis. These mechanistic insights not only reinforce the association between smoking and risk for rheumatoid arthritis, but also the necessity to increase the level of awareness in those at highest risk.

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Section: Anti-inflammatory/immunosuppressive Therapiesmentioning

confidence: 99%

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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“…It is interesting to observe that ligands from NCIDS3 are in similar predicted binding affinity window as the known PAD4 inhibitors [15]. The plot of number of ligands with respect to their binding affinity range as shown in Figure 4 followed a bell-shaped trend, with majority population lies within the range of -6.0 kcal/mol.…”

Section: Structure-based Virtual Screening Of Ncids3mentioning

confidence: 84%

“…Here in our case, we look forward to ensure that the protocol was suitable and reliable to distinguish and rank PAD4 inhibitors. To achieve the goal, a set of compounds with known PAD4 inhibitions (here labeled as S1 to S12) reported by Bozdag et al was used [15]. Table 1 showed the experimental inhibition, experimental rank, predicted binding affinity and predicted rank for compounds S1-S12.…”

Section: Results and Discussion Validation Of Docking Parametersmentioning

confidence: 99%

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In-Silico Identification of Potential Protein Arginine Deiminase Iv (Pad4) Inhibitors

Rahman¹

2016

MJAS

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Protein Arginine Deiminase IV (PAD4) is a promising target for treating rheumatoid arthritis. Here, an in-silico screening was performed using PAD4 crystal structure against National Cancer Institute Diversity Set III compounds. Results obtained from the docking studies showed that the compounds have high affinity towards the protein. Visual inspections of the top compounds indicated that they preferred to bind at the front door of the catalytic pocket instead of the back door. The current results from this screening could provide a basis for the development of new PAD4 inhibitors.Keywords: protein arginine deiminase IV, PAD4, virtual screening, NCI diversity set, structure-based Abstrak Protin arginina deiminase IV (PAD4) adalah sasaran yang berharapan untuk merawat artritis reumatoid. Di sini, satu saringan insilico telah dilakukan menggunakan struktur kristal PAD4 terhadap molekul dari Set Beraneka Institut Kanser Nasional III. Keputusan dari pengdokan molekular menunjukkan molekul-molekul tersebut mempunyai daya tarikan yang tinggi terhadap protin. Pemeriksaan secara visual ke atas molekul teratas menunjukkan mereka mempunyai kecenderungan untuk terikat di pintu hadapan poket katalisis daripada di pintu belakang. Keputusan daripada pencarian ini boleh menjadi asas kepada penemuan perencat PAD4 yang baru.

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“…These neurodegenerative iPSC models will be useful functional tools for continuing studies on effects of PAD-mediated EV shedding, and the efficacy of pharmacological modulation of PAD-mediated mechanisms to ameliorate neurodegenerative disease pathologies. While Cl-Am [141] remains the most used experimental inhibitor to date, the therapeutic potential and generation of second generation and selective isozyme-specific PAD inhibitors is receiving ever increasing attention [72,82,[142][143][144][145][146]. Ongoing work aims at dissecting the roles of individual PAD isozymes in EV biogenesis, to identify further deiminated key target proteins, assess the epigenetic impact of histone deimination, and to evaluate disease-specific EV cargo.…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors

Cited by 34 publications

References 46 publications

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

In-Silico Identification of Potential Protein Arginine Deiminase Iv (Pad4) Inhibitors

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

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