madman
Super Moderator
Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors
ABSTRACT
Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiological processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing them for a wider range of clinical applications.
1. Introduction
The cGMP-binding, cGMP-specific phosphodiesterase 5 (PDE5) is a key regulator of cGMP signaling in the cardiovascular and other tissues. Typically, cGMP signal transduction pathway in a cell is initiated by ligand-mediated activation of a guanylyl cyclase (GC) enzyme, either soluble or receptor, resulting in an increased production of cGMP, which exerts its effect through activating effectors such as cGMP-dependent protein kinase G (PKG) and cGMP-regulated ion channels (Fig. 1). In this way, cGMP signaling pathway regulates a number of physiological processes including vascular tone, visual signal transduction, energy metabolism, renal function, intestinal fluid secretion, gut peristalsis, lipolysis, oocyte maturation, cerebellar motor control, transcription, cell growth, cell motility, anti-inflammatory activity, and apoptosis [1–9]. Several of these processes are regulated by the action of PDE5, which is allosterically activated by the increased level of cGMP in these cells via cGMP binding to its regulatory domain, resulting in enhanced activity of the PDE5 catalytic domain, and subsequently, bringing the intracellular cGMP concentration to the basal levels. As a prerequisite for its function, PDE5 is expressed in a variety of tissues including the lung, brain, kidney, cardiac myocytes, gastrointestinal tissue, vascular smooth muscle cells, platelets, and penile corpus cavernosum [7,10–19]. In addition to the cGMP-mediated allosteric activation, the PDE5 function is regulated at the genetic level through the expression of various isoforms as well as by post-translational modifications such as phosphorylation, which also results in its activation [12,20] and nitrosylation, which results in its degradation through the ubiquitin pathway [21]. Specifically, PDE5 targets cGMP generated by nitric oxide (NO)- activated soluble GC [22] by catalyzing the hydrolysis of a phosphodiester bond in cGMP through its catalytic domain, thereby converting cGMP to the inactive 5’-GMP form [23] (Fig. 1). In addition to the catalytic domain, which is located at the C-terminal of the protein, PDE5 contains regulatory GAF (mammalian cGMP-dependent phosphodiesterase, Anabaena adenylyl cyclase, and E. coli FhlA) domains (GAFa-GAFb) in tandem in the N-terminal side. While structurally similar, the GAF domains in PDE5 play distinct roles. The N-terminal GAFa domain binds cGMP and allosterically modulates the catalytic domain activity [24], while the C-terminal GAFb domain plays a role in the dimerization of the enzyme [25].
Given its critical role in cGMP signaling, PDE5 has been pharmacologically targeted for the treatment of a number of pathological conditions including erectile dysfunction and pulmonary arterial hypertension [8,26,27]. The development and successful clinical application of a number of PDE5 inhibitors, such as sildenafil, to regulate cGMP levels in penile corpus cavernosum for the treatment of erectile dysfunction is a prime example of pharmacological targeting of proteins in the cGMP signal transduction pathway [28–31]. Importantly, these inhibitors of PDE5 were later approved for other clinical applications, such as pulmonary arterial hypertension (PAH) and lower urinary tract symptoms (LUTS) [32–34], while efforts to expand their clinical use to other diseases are still ongoing. In this review article, we outline the role of PDE5 in the cGMP signal transduction pathway and describe its inhibitors that are in clinical use. Specifically, we will describe the structural features of the protein, how its activity is regulated, and the pharmacological inhibitors that are used in its targeting. We envisage that this overview will highlight the mechanistic approach by which PDE5 inhibitors selectively bind to the enzyme and will guide future endeavors toward the development of selective and potent inhibitors of this key cGMP regulator.
2. Structural and regulatory features in PDE5
3. PDE5 inhibitors
3.1. Sildenafil
3.2. Vardenafil
3.3. Tadalafil
3.4. Avanafil
4. Clinical applications of PDE5 inhibitors
5. Conclusion
PDE5 plays a key role in regulating a multitude of cGMP-mediated physiological processes involving multiple regulatory mechanisms including allosteric structural changes and posttranslational modifications such as phosphorylation. Unsurprisingly, it has been targeted with a variety of pharmacological inhibitors for the treatment of a number of diseases including erectile dysfunction and pulmonary hypertension. First, understanding the binding interaction of these inhibitors with the active site and the structural bases of their affinity and selectivity will provide a great advantage in the design of novel potent and highly selective PDE5 inhibitors. Second, while PDE5 inhibitors have several therapeutic applications, only three of these therapeutic applications are FDA-approved. There is increasing evidence that PDE5 inhibitors could play a role in the management of a number of additional diseases including cancer and COVID-19 complications by modulating the NO-cGMP-PDE5 axis, suggesting their use as adjuncts in the treatment of COVID-19 infection. However, clinical studies are warranted in order to extend the therapeutic applications of these inhibitors to a wider range of diseases. Further, much remains to be explored with respect to allosteric regulation, specifically through pharmacological agents, of PDE5 that can be employed for fine-tuning its activity in a tissue and disease context-dependent manner.
ABSTRACT
Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiological processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing them for a wider range of clinical applications.
1. Introduction
The cGMP-binding, cGMP-specific phosphodiesterase 5 (PDE5) is a key regulator of cGMP signaling in the cardiovascular and other tissues. Typically, cGMP signal transduction pathway in a cell is initiated by ligand-mediated activation of a guanylyl cyclase (GC) enzyme, either soluble or receptor, resulting in an increased production of cGMP, which exerts its effect through activating effectors such as cGMP-dependent protein kinase G (PKG) and cGMP-regulated ion channels (Fig. 1). In this way, cGMP signaling pathway regulates a number of physiological processes including vascular tone, visual signal transduction, energy metabolism, renal function, intestinal fluid secretion, gut peristalsis, lipolysis, oocyte maturation, cerebellar motor control, transcription, cell growth, cell motility, anti-inflammatory activity, and apoptosis [1–9]. Several of these processes are regulated by the action of PDE5, which is allosterically activated by the increased level of cGMP in these cells via cGMP binding to its regulatory domain, resulting in enhanced activity of the PDE5 catalytic domain, and subsequently, bringing the intracellular cGMP concentration to the basal levels. As a prerequisite for its function, PDE5 is expressed in a variety of tissues including the lung, brain, kidney, cardiac myocytes, gastrointestinal tissue, vascular smooth muscle cells, platelets, and penile corpus cavernosum [7,10–19]. In addition to the cGMP-mediated allosteric activation, the PDE5 function is regulated at the genetic level through the expression of various isoforms as well as by post-translational modifications such as phosphorylation, which also results in its activation [12,20] and nitrosylation, which results in its degradation through the ubiquitin pathway [21]. Specifically, PDE5 targets cGMP generated by nitric oxide (NO)- activated soluble GC [22] by catalyzing the hydrolysis of a phosphodiester bond in cGMP through its catalytic domain, thereby converting cGMP to the inactive 5’-GMP form [23] (Fig. 1). In addition to the catalytic domain, which is located at the C-terminal of the protein, PDE5 contains regulatory GAF (mammalian cGMP-dependent phosphodiesterase, Anabaena adenylyl cyclase, and E. coli FhlA) domains (GAFa-GAFb) in tandem in the N-terminal side. While structurally similar, the GAF domains in PDE5 play distinct roles. The N-terminal GAFa domain binds cGMP and allosterically modulates the catalytic domain activity [24], while the C-terminal GAFb domain plays a role in the dimerization of the enzyme [25].
Given its critical role in cGMP signaling, PDE5 has been pharmacologically targeted for the treatment of a number of pathological conditions including erectile dysfunction and pulmonary arterial hypertension [8,26,27]. The development and successful clinical application of a number of PDE5 inhibitors, such as sildenafil, to regulate cGMP levels in penile corpus cavernosum for the treatment of erectile dysfunction is a prime example of pharmacological targeting of proteins in the cGMP signal transduction pathway [28–31]. Importantly, these inhibitors of PDE5 were later approved for other clinical applications, such as pulmonary arterial hypertension (PAH) and lower urinary tract symptoms (LUTS) [32–34], while efforts to expand their clinical use to other diseases are still ongoing. In this review article, we outline the role of PDE5 in the cGMP signal transduction pathway and describe its inhibitors that are in clinical use. Specifically, we will describe the structural features of the protein, how its activity is regulated, and the pharmacological inhibitors that are used in its targeting. We envisage that this overview will highlight the mechanistic approach by which PDE5 inhibitors selectively bind to the enzyme and will guide future endeavors toward the development of selective and potent inhibitors of this key cGMP regulator.
2. Structural and regulatory features in PDE5
3. PDE5 inhibitors
3.1. Sildenafil
3.2. Vardenafil
3.3. Tadalafil
3.4. Avanafil
4. Clinical applications of PDE5 inhibitors
5. Conclusion
PDE5 plays a key role in regulating a multitude of cGMP-mediated physiological processes involving multiple regulatory mechanisms including allosteric structural changes and posttranslational modifications such as phosphorylation. Unsurprisingly, it has been targeted with a variety of pharmacological inhibitors for the treatment of a number of diseases including erectile dysfunction and pulmonary hypertension. First, understanding the binding interaction of these inhibitors with the active site and the structural bases of their affinity and selectivity will provide a great advantage in the design of novel potent and highly selective PDE5 inhibitors. Second, while PDE5 inhibitors have several therapeutic applications, only three of these therapeutic applications are FDA-approved. There is increasing evidence that PDE5 inhibitors could play a role in the management of a number of additional diseases including cancer and COVID-19 complications by modulating the NO-cGMP-PDE5 axis, suggesting their use as adjuncts in the treatment of COVID-19 infection. However, clinical studies are warranted in order to extend the therapeutic applications of these inhibitors to a wider range of diseases. Further, much remains to be explored with respect to allosteric regulation, specifically through pharmacological agents, of PDE5 that can be employed for fine-tuning its activity in a tissue and disease context-dependent manner.
