Cardiovascular Disorders

Cardiovascular disorders, such as atherosclerosis, myocardial infarction, and heart failure, continue to pose significant global health challenges. As a leading Preclinical CRO, Alfa Cytology has dedicated significant efforts to exploring novel poly(ADP-ribose) polymerase (PARP) inhibitor to combat cardiovascular disorders.

Introduction to PARP Inhibitor for Cardiovascular Disorders

PARP, particularly the predominant isoform PARP1, plays a crucial role in the cellular response to DNA damage. Upon detection of DNA breaks, PARP1 becomes activated, leading to the addition of poly(ADP-ribose) (PAR) chains to various nuclear proteins. This initiates a cascade of DNA repair mechanisms. However, in the context of cardiovascular disorders, excessive PARP1 activation can have detrimental consequences, including the depletion of cellular energy stores, such as nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP), ultimately resulting in inflammation, SIRT 1 necrosis, endothelial dysfunction, oxidized LDL cholesterol, and apoptosis.

Fig. 1 Emerging role of PARP in cardiovascular disorders. (Ahmad A., et al. 2019)

PARP Inhibitor Development for Cardiovascular Disorders

By utilizing in vivo and in vitro models, the researchers investigated the efficacy as well as the mechanism of action of clinically approved PARP inhibitors, such as olaparib, repurposed for the treatment of cardiovascular disease. The results suggest that PARP inhibitors could be further utilized in the development of new treatments for cardiovascular disease.

Experimental Model	Disease Modelled	PARP Inhibitor	Effects
H9c2 cells subjected to oxidative stress	Myocardial infarction	Olaparib	Protection against cell death and mitochondrial dysfunction
HL-1 cardiomyocytes or isolated rat atrial cardiomyocytes subjected to tachypacing	Atrial fibrillation, cardiac arrhythmias	Olaparib or Veliparib	Protection against NAD+ depletion and oxidative protein/DNA damage, prevention of channel remodelling and improved electrophysiology
hVSMCs or MC3T3 cells subjected to calcification-inducing conditions	Vascular calcification, atherosclerosis	Olaparib, Veliparib or Rucaparib	Inhibition of vascular calcification
C. elegans with ATM mutation	Ataxia telangiectasia	Olaparib	Improvement of movement and memory
Drosophila prepupae subjected to tachypacing	Atrial fibrillation	Olaparib or Veliparib	Protection against NAD+ depletion and improved cardiac contractility

Our Services

At Alfa Cytology, our team of highly skilled biological specialists offers a comprehensive range of services to support the development of PARP inhibitors for cardiovascular disorders.

Preclinical Discovery

Small Molecule Inhibitor Development

Designing and synthesizing potent and selective small molecule PARP inhibitors.
Employing structure-based drug design (SBDD) techniques to target the PARP catalytic domain.

Peptide Inhibitor Development

Exploring the potential of peptide-based PARP inhibitors.
Leveraging expertise in peptide design and optimization for selective PARP modulation.

Structure-Based Drug Design (SBDD)

Applying computational modeling, X-ray crystallography, and molecular dynamics simulations.
Gaining insights into PARP-inhibitor structural interactions to optimize potency, selectivity, and pharmacokinetics.

Preclinical Research

Cardiovascular Disease Models

Providing in vitro and in vivo models for evaluating the efficacy of PARP inhibitors in cardiovascular disease.
Optional Species: Mouse, Rats, Zebrafish, C. elegans, Drosophila, Non-human primates, and Others.

Pharmacokinetic and Pharmacodynamic (PK/PD) Studies

Investigating the absorption, distribution, metabolism, and excretion of PARP inhibitors
Assessing the corresponding pharmacodynamic effects to inform dose selection and dosing regimens.

Toxicology Studies

Evaluating the cytotoxicity, genotoxicity, acute and chronic toxicology of PARP inhibitors in relevant models.

Alfa Cytology is committed to advancing the field of cardiovascular disorders research and driving the development of novel PARP inhibitor. To achieve this goal, we actively engage in collaborative efforts with leading academic institutions and pharmaceutical companies. For more information about our PARP inhibitor development program for sepsis or to discuss potential collaborations, please don't hesitate to contact us.

Reference

Henning RJ, Bourgeois M, Harbison RD. Poly (ADP-ribose) Polymerase (PARP) and PARP Inhibitors: Mechanisms of Action and Role in Cardiovascular Disorders. Cardiovasc Toxicol. 2018, 18(6): 493-506.

For research use only. Not intended for any clinical use.