Beyond ED: cGMP-Specific PDE5i for Other Clinical Disorders

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Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders (2022)
Arun Samidurai, Lei Xi, Anindita Das, and Rakesh C. Kukreja


Abstract

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide–driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer’s disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.




INTRODUCTION

Cellular levels of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are maintained by a family of enzymes named cyclic nucleotide phosphodiesterases (PDEs) (1–3). The PDEs degrade the phosphodiester bond of 3 -5 -cAMP and 3 -5 -cGMP and convert them to their inactive forms: 5 -AMP and 5 -GMP, respectively (4). The PDEs are broadly classified into 11 different families, PDE1–PDE11, largely on the basis of their structure, function, and substrate specificity. PDE4, PDE7, and PDE8 hydrolyze cAMP exclusively, whereas PDE5, PDE6, and PDE9 hydrolyze cGMP (2). PDE1, PDE2, PDE3, PDE10, and PDE11 can hydrolyze both cAMP and cGMP.

PDE5, the focus of this review, encompasses several key features of PDEs, including the conserved carboxy-terminal end and a variable regulatory amino-terminal domain, which are present in cGMP-specific PDEs. The regulatory region of PDE5 contains two GAF domains (GAF-A and GAF-B) that control the catalytic activity and dimerization of the protein (5, 6). GAF domains are named on the basis of certain proteins in which they are found: cGMP-specific PDEs, adenylyl cyclases, and FhlA. The binding of cGMP to the GAF-A nucleotide pocket allosterically modulates the catalytic activity (7), and the C-terminal GAF-B domain plays a role in the dimerization of the PDE5 enzyme (8).

Humans express three PDE5 isoforms: PDE5A1, PDE5A2, and PDE5A3 (Figure 1a). The variants may allow for differential control of PDE5A gene expression in various cells. In humans, the PDE5A gene is located on chromosome 4q26, a region that reportedly codes for three isoforms: PDE5A1, PDE5A2, and PDE5A3 (9, 10). PDE5A1 and PDE5A2 are expressed in most tissue types, whereas PDE5A3 is confined to smooth muscle cells. All three isoforms vary in their amino acid composition at the N terminus. PDE5 is abundantly expressed in the smooth muscle cells of the corpus cavernosum and cardiovascular system (5, 6). PDE5 is also expressed in vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, spinal cord, cerebellum, pancreas, prostate, urethra, and bladder (11, 12). Although PDE5 is present in coronary vascular smooth muscle cells (13), healthy myocardium does not express high levels of the enzyme (14). However, upregulation of PDE5 has been detected in congestive heart failure (HF) and right ventricular (RV) hypertrophy (15, 16).

Because cGMP levels modulate vascular tone, it is an obvious target for therapeutic intervention in multiple diseases. Sildenafil citrate was the first PDE5 inhibitor approved for the treatment of erectile dysfunction (ED). As shown in Figure 1b, in addition to sildenafil, three other drugs are approved by the US Food and Drug Administration (FDA) for ED: tadalafil, vardenafil, and avanafil. Clinically available but non-FDA-approved PDE5 inhibitors for ED include lodenafil, udenafil, and mirodenafil; these drugs are available in some countries. When a man is sexually stimulated, either physically or psychologically, nitric oxide (NO) is released from noncholinergic, and nonadrenergic neurons in the penis and from endothelial cells (17). NO diffuses into cells and activates soluble guanylyl cyclase, which converts GTP to cGMP, thereby stimulating protein kinase G (PKG), which initiates a protein phosphorylation cascade. This cascade results in a decrease in intracellular levels of calcium ions, ultimately dilating the arteries that bring blood to the penis and compressing the spongy corpus cavernosum (Figure 2). PDE5 inhibitor blocks enzymatic hydrolysis of cGMP in the corpus cavernosum, resulting in a similar outcome. Currently, the clinically approved indications of PDE5 inhibitors also include lower urinary tract symptoms (LUTSs) and pulmonary arterial hypertension (PAH). In addition, many preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, HF, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy (DMD), Alzheimer’s disease (AD), and other aging-related conditions.




*PDE5 IN PULMONARY ARTERIAL HYPERTENSION


*PDE5 IN ISCHEMIA/REPERFUSION INJURY


*PDE5 INHIBITORS IN HEART FAILURE


*PDE5 IN DUCHENNE AND BECKER MUSCULAR DYSTROPHY


*PDE5 IN ENDOTHELIAL DYSFUNCTION, METABOLISM, AND DIABETES


*PDE5 IN CANCER


*PDE5 IN AGING-RELATED DISEASES AND CONDITIONS


*PDE5 IN ALZHEIMER’S DISEASE AND NEURODEGENERATIVE DISORDERS


*PDE5 IN BLADDER DYSFUNCTION AND BENIGN PROSTATIC HYPERPLASIA


*THERAPEUTIC PROSPECTS OF PDE5 INHIBITORS IN COVID-19


*POTENTIAL ADVERSE EFFECTS OF PDE5 INHIBITORS




CONCLUDING REMARKS

The dysregulation of NO-cGMP-PKG signaling plays a critical role in a variety of diseases, including urological disorders, cardiovascular disorders, cancer, aging-related complications, and genetic disorders, such as DMD. PDE5 inhibitors have played an important role in improving the quality of life for men (being first-line therapy in ED) and in treating PAH and LUTS. PDE5 is expressed in many tissues, which implies the potential for new indications for PDE5 inhibitors. Experimental data, and to a lesser extent clinical studies, suggest that PDE5 inhibitors are cardioprotective in the setting of I/R injury, HF, diabetes, and cancer. There is also growing evidence that PDE5 inhibitors have the potential to treat aging-related diseases, including AD, and as an adjunct therapy to improve COVID-19 outcomes by modulating the NO-cGMP-PDE5 axis. In consideration of the established safety record of PDE5 inhibitors, repurposing these drugs may offer an attractive option for future treatments of many human diseases.

 

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Figure 1 (a) Basic domain arrangement of phosphodiesterase 5 (PDE5) enzyme with three identified PDE5 isoforms (i.e., PDE5A1, PDE5A2, PDE5A3). Note that the key features of PDEs include the conserved carboxy-terminal end and a variable regulatory amino-terminal domain. The regulatory region of PDE5 contains two GAF domains (GAF-A and GAF-B) that control catalytic activity and dimerization of the protein. The binding of cyclic guanosine monophosphate (cGMP) to the GAF-A nucleotide pocket allosterically modulates the catalytic activity, while the C-terminal GAF-B domain plays a role in the dimerization of the PDE5 enzyme. (b) Chemical structures of the commonly used inhibitors of PDE5, which include those administered in humans as the US Food and Drug Administration–approved therapies for the management of erectile dysfunction, pulmonary arterial hypertension, and lower urinary tract symptoms. Compounds 1–9 are newly synthesized compounds for potential therapeutic use for neurodegenerative diseases. Compounds 1, 3, and 5–9 adapted with permission from Reference 182. CM-414 adapted with permission from Reference 199.

 

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Figure 2 PDE5 as a therapeutic target for erectile dysfunction. Sexual stimulation releases NO from noncholinergic, and nonadrenergic neurons in the penis and from endothelial cells. NO diffuses into cells and activates soluble GC, which converts GTP to cGMP. The cyclic nucleotide then stimulates PKG, which initiates a protein phosphorylation cascade, thereby decreasing intracellular levels of calcium ions, ultimately dilating the arteries that bring blood to the penis and compressing the spongy corpus cavernosum. PDE5 is the target for sildenafil and other PDE5 inhibitors for the treatment of erectile dysfunction. Abbreviations: cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate, eNOS, endothelial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PDE5, phosphodiesterase 5; PKG, protein kinase G; sGC, soluble guanylyl cyclase.

 

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Figure 3 Cardioprotective pathways of NO-cGMP-PKG signaling in ischemic injury and cardiac hypertrophy. NO and cGMP generation by inhibition of PDE5 or activation of sGC triggers PKG signaling, which protects the heart by phosphorylating Akt, ERK1/2, and pGSK3β and inducing Bcl-2 as well as the opening of mito-KATP channels. PKG activation also reduces ROS generation via AMPK– Sirt1–PGC-1α signaling, which protects the heart against cardiac hypertrophy and myocardial infarction. The antihypertrophic effect is also associated with the activation of PKG, and its targets include regulators of G protein–coupled signaling-2 as well as calcineurinNFAT and TRP6. PKG activation also provides posttranslational enhancement of protein quality control through the facilitation of protein degradation via the proteasome and autophagy-lysosome-dependent pathways in the ischemic heart. Abbreviations: AMPK, AMPactivated protein kinase; Ang-I, angiopoietin-1; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; CHIP, C-terminal Hsp70-interacting protein; CNP, C-type natriuretic peptide; ERK, extracellular signal-regulated kinase; GTP-guanosine triphosphate; HSc70, Heat shock cognate 71 kDa protein; mito-KATP, ATP-sensitive mitochondrial potassium channel; MPTP, mitochondrial permeability transition pore; NFAT, nuclear factor of activated T cells; NO, nitric oxide; PDE5, phosphodiesterase 5; pGSK3β, phospho-glycogen synthase kinase-3β; pGC, particulate guanylate cyclase; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator; pGSK3β, phosphorylated glycogen synthase kinase-3β; PKG, protein kinase G; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; Sirt1, sirtuin 1; TRP6, transient receptor potential channel 6; VEGF, vascular endothelial growth factor.

 

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Figure 4 Role of PDE5 in regulation of metabolic diseases. Maintenance of cGMP-PKG pathway by PDE5 inhibition is critical for improving endothelial and metabolic function and browning of adipose tissue of WAT through increased expression of UCP1 and PGC-1α, leading to mitochondrial biogenesis. PKG controls insulin signaling in BAT by inhibiting RhoA activity and ROCK, thereby removing its inhibitory effects on IRS-1 and activating the downstream PI3-kinase–Akt cascade. Abbreviations: ANP, atrial natriuretic peptide; BAT, brown adipose tissue; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; CNP, C-type natriuretic peptide; CREB; cAMP-response element binding protein; IR, insulin receptor; IRS-1, insulin receptor substrate-1; PDE5, phosphodiesterase 5; PDE5i, PDE5 inhibitor; pGC, particulate guanylate cyclase; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; PI3K, phosphatidylinositol-3 kinase; PKG, protein kinase G; ROCK, Rho-associated kinase; UCP1, uncoupling protein 1; WAT, white adipose tissue.

 

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Table 1 List of various types of cancers responsive to PDE5 inhibitors and their mechanism(s) of action as either single agent or adjuvant therapy with other cancer drugs.

 

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Figure 5 PDE5 inhibitors and anticancer signaling. The NO-cGMP signaling triggered by PDE5 inhibition inhibits β-catenin and increases the killing of multiple types of cancers. PDE5 inhibitors also enhance the effectiveness of multiple chemotherapeutics, including doxorubicin, by increasing their intracellular accumulation through inhibition of ABC transporter–mediated efflux. Abbreviations: ABCG1/2, ATP-binding cassette subfamily G 1/2; cGMP, cyclic guanosine monophosphate; MDSC, myeloid-derived suppressor cell; NO, nitric oxide; PDE5, phosphodiesterase 5; PDEi, PDE inhibitor; PKG, protein kinase G; pGC, particulate guanylate cyclase; sGC, soluble guanylate cyclase.

 

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Figure 6 Role of novel inhibitors targeting cGMP-PKG in the treatment of AD. Intracellular amyloid plaques consisting of Aβ aggregates and extracellular neurofibrillary tangles are formed by hyperphosphorylated tau fibrils, which affect neuronal functioning in AD. PDE5 inhibitors may attenuate neuronal apoptosis through the inhibition of neuroplasticity-related molecules, including BDNF and Aβ peptide. Novel compounds 1 and 3 are PDE5-specific inhibitors and can readily cross the blood-brain barrier with enhanced efficacy in mouse models of AD. Compound CM-414, a dual inhibitor of HDACs and PDE5, has synergistic therapeutic efficacy in AD models. Compounds 5 and 6 are also dual inhibitors that target both PDE5 and HDACs in AD. Compounds 7–9 are dual inhibitors of AChE and PDE5. Abbreviations: Aβ, amyloid-β; AChE, acetylcholine esterase; AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor; cGMP, cyclic guanosine monophosphate; GSK3β, glycogen synthase kinase-3β; GTP, guanosine triphosphate; HDAC, histone deacetylase; pCREB, phosphorylated cAMP-response element binding protein; PDE5, phosphodiesterase 5; PDE5i, PDE5 inhibitor; pGC, particulate guanylate cyclase; PKG, protein kinase G; sGC, soluble guanylate cyclase.

 

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Figure 7 PDE5 inhibition in the treatment of COVID-19 and pulmonary hypertension. The binding of the SARS-CoV-2 virus with its ACE2 receptor leads to excessive activation of the ACE–angiotensin II–angiotensin type 1 receptor pathway. Angiotensin II stimulates ROS with the potential depletion of NO, which triggers a proinflammatory cascade for vasoconstriction. The NO-cGMP-PKG pathway activated by treatment with PDE5 inhibitors restores NO through AMPK-mediated eNOS activation, thereby attenuating inflammation and inhibiting of platelet aggregation. PDE5 inhibitors also significantly increase pulmonary vasorelaxation and attenuate pulmonary arterial hypertension. Abbreviations: ACE2, angiotensin-converting enzyme 2; AMPK, AMP-activated protein kinase; Ang I/II, angiotensin I/II; AT1R/AT2R, angiotensin II receptor type 1/2 receptor; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; NO, nitric oxide; PDE5, phosphodiesterase 5; pGC, particulate guanylate cyclase; PKG, protein kinase G; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; sGC, soluble guanylate cyclase.

 

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SUMMARY POINTS

1. Phosphodiesterase 5 (PDE5) is involved in the pathophysiology of several diseases due to dysregulated nitric oxide–cGMP–protein kinase G signaling

2. Because of the widespread expression of PDE5 in numerous tissues and organs, it is a target for the potential treatment of various diseases

3. PDE5 inhibitors, including sildenafil, are clinically used to manage erectile dysfunction, pulmonary arterial hypertension, and lower urinary tract symptoms of benign prostatic hyperplasia

4. Experimental results and some clinical data suggest the potential for PDE5 inhibitors in the treatment of diseases that include cardiovascular disorders, Alzheimer’s disease, and cancer, among others