Multi-Target Drugs For Kidney Diseases
Apr 20, 2023
Abstract
Renal diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathology of kidney disease is very complex, progresses at different rates, and involves multiple cell types and cell signaling pathways. Complex renal diseases require therapeutic approaches that can act on multiple targets. In the last decade, drug-on-a-chip design has led to the rapid development of multi-targeted drugs from concept to reality. Several multi-targeted drugs targeting AA pathways and transcription factors have been successfully used to treat inflammatory, fibrotic, and metabolic diseases. Multi-targeted drugs have also shown great potential for the treatment of diabetic nephropathy and fibrotic nephropathy. These drugs act by reducing renal TGF-b signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-targeted agents that have not been tested for their ability to combat renal disease. Overall, there is great potential for multi-targeted drugs to act on multiple cell types and signaling pathways to treat kidney disease.
Click here to know what are the Cistanche and the effects of Cistanche
It is estimated that 37 million people in the United States have kidney disease and that Medicare spends more than $130 billion to treat kidney disease. Types of kidney disease include AKI, CKD, and GN. The major risk factors for kidney disease are hypertension, diabetes, and family history. Cardiovascular disease and high morbidity and mortality are associated with kidney disease. Despite the severity of kidney disease, treatment options are limited and many patients require dialysis and kidney transplantation.
AKI, CKD, and glomerular disease have a variety of etiologies. Causes of AKI include drug toxicity, thoracic surgical ischemia, and septic infections. The pathophysiology of AKI includes systemic hypotension, systemic hypoxia, and reduced blood oxygen supply due to disruption of local oxygen delivery to the kidney. Signaling and metabolic pathways in renal tubular segments and epithelial cells include activation of hypoxia-inducible factors, activation of the peroxisome proliferator-activated receptor g (PPARg) -PPARg coactivator 1a (PGC-1a) pathway, mitochondrial signaling, and fructokinase activation.CKD is primarily due to hypertension and diabetes mellitus leading to progressive renal damage through very different cellular mechanisms. Diabetic nephropathy results from oxidative stress, inflammation, mitochondrial dysfunction, and fatty acid metabolism leading to renal fibrosis that impairs renal tubular transport, renal hemodynamics, and glomerular filtration. Glomerular disease, such as glomerulonephritis, starts with glomerular injury, which can then lead to extra-glomerular structural kidney injury. Immune complexes and complement components, such as C3 and C5, can lead to glomerular inflammatory cell infiltration. Glomerular thylakoid cells, podocytes, and endothelial cells are damaged, and an increased extracellular matrix leads to glomerulosclerosis. Subsequently, non-immune mechanisms lead to progressive renal damage resulting in interstitial fibrosis. Overall, renal diseases are extremely complex because they involve multiple cell types, and multiple cellular signaling pathways, and progress at different rates.
Cistanche Supplements
The complexity of renal disease requires the development of therapeutic approaches that can act on multiple targets (Figure 1). Renal diseases, such as AKI, diabetic nephropathy, CKD, FSGS, GN, and ESKD, involve multiple renal cell types and disease progression depends on changes in many cellular signaling pathways. In recent years, the emergence of multi-targeted drugs has led to new therapies for the treatment of renal diseases.
Designing Multi-Target Small-Molecule Drugs for Kidney Diseases
Thoughtful and rational design of drugs for multiple targets has gained momentum in the last decade. Biological systems have built-in compensatory mechanisms and redundant functions that allow them to resist single-point perturbations; thus, diseases are often caused by multiple genetic and/or environmental factors that contribute to the failure of physiological systems. Complex diseases, such as metabolic diseases, fibrotic diseases, AKI, CKD, and glomerular diseases, are more likely to be treated by simultaneous modulation of multiple targets.
The approval of sulpiride/valsartan, a combination of neprilysin and angiotensin type 1 (AT1) receptor inhibitor for the treatment of heart failure, inspired the concept of developing dual-acting molecules for the treatment of kidney disease. Our group and others have focused on molecular pathways for dual-acting small molecules targeting organ fibrosis and life-threatening kidney disease. These multi-target drugs have greater potential than single-target and highly specific drugs because of (1) better disease-modifying effects, (2) additive and/or synergistic therapeutic effects, (3) more predictable pharmacokinetics than combination therapy, (4) longer effective duration, and (5) lower potential for drug interactions (Table 1). It is increasingly recognized that balanced modulation of both targets can provide superior therapeutic efficacy and side effects.
Types of Multi-Target Drugs
A major challenge in developing multi-target drugs (also known as multi-ligand drugs) is the need to optimize the drug for multiple biological targets while maintaining appropriate drug properties. On average, multi-target drugs have greater molar wattage and are more lipophilic than compounds designed to modulate a single target. Although multi-target drugs have been developed with appropriate drug-like properties, a key aspect of the drug design and development process is the selection of biological targets. Computational tools and structural information allow for pharmacophore modeling, enabling the design of multi-targeted drugs that are selective for the intended biological target. Determining the required activity balance, balancing pharmacological properties and biological target selectivity is another major challenge in the development of multi-targeted drugs.
Multi-target drugs can be divided into three main categories: linked, fused, and combined pharmacophore drugs (Figure 2). Linked multi-target drugs consist of two different pharmacophores for each target that are connected by a linker. These linked multi-target drugs tend to have larger molar weights. Sulbactrim/valsartan is an example of a linked multi-target drug with a unique pharmacophore that inhibits the neprilysin enzyme and a unique pharmacophore that antagonizes the AT1 receptor. Reducing the size of the linker of a linked multitarget drug eventually leads to essential contact of the pharmacophore, resulting in a fused multitarget drug. Thus, fused multitargeted drugs have different pharmacodynamic clusters that are not separated by linkers. The disadvantages of linked and fused multitargeted drugs are large molar weights and extensive lipophilicity. Combined multi-target drugs are based on a common, combined pharmacophore designed to engage a biological target of interest while having a low molar weight and meeting other aspects of Lipinski's rule. The design and optimization of multi-targeted combined pharmacophore drugs have been the most challenging to date. The emergence of unambiguous drug structure-activity relationships through x-ray structural information and microarray design of protein targets can help find the starting point for merging multi-target drugs. Several multitargeted drugs with linked, fused, or combined pharmacophores have been developed and tested for their ability to combat renal disease using cell-based and animal models.
Progress with Multi-Target Drugs for Kidney Diseases
A key step in the design of multi-targeted drugs for kidney disease is the identification of molecular targets. The targets must be disease modifications that attack different signaling pathways or the same signaling pathway from different angles. For example, in renal disease, one mechanism of interest is blocking TGF-b signaling that leads to fibrosis. The key signaling cascade response is primarily initiated by TGF-b but also involves inflammatory cytokines and signaling molecules that stimulate a pro-fibrotic response in myofibroblasts and are potential therapeutic targets. Because TGF-b plays a key role in fiber formation, it was initially thought that targeting TGFb could control organ fibrosis. Unfortunately, this approach failed because TGF-b also plays a crucial role in many important biological processes, such as immunity and cell growth. Therefore, the ideal approach to treat fibrotic nephropathy is to modulate several downstream mechanisms without blocking important TGF-b-regulated biological processes. Multi-targeted drugs for renal disease target transcription factors, AA metabolites, entertain g protein-coupled receptors, and the renin-angiotensin system.
Cistanche extract
Over the past 5 years, the evaluation of multi-targeted agents for the renal disease has been expanding. These efforts have focused on diabetes and hypertension CKD and renal fibrosis. Multi-target drugs can treat not only kidney disease but also diabetes, metabolic disease, and hypertension simultaneously. This is achieved by an initial comparison of multi-target drugs with their respective single-target approaches in enzymatic or cellular systems. Because target combinations in CKD involve individual targets expressed in different tissues of the body, in vivo validation of anti-CKD multi-target drugs is required. This is an important hurdle, as reaching this step requires significant medicinal chemistry efforts to develop multi-target drugs that selectively modulate individual targets of interest while maintaining appropriate pharmacokinetic properties. Excitingly, the high-risk, high-reward development of multi-target drugs for the treatment of kidney disease has led to a number of promising agents approaching or already in human clinical trials.
Drugs that modulate the AA pathway have anti-inflammatory, anti-fibrotic, anti-hypertensive, and anti-diabetic effects and have the potential to treat kidney disease. One of the major pathways utilized in multi-targeted drugs is the cyclooxygenase pathway. Inhibition of the enzyme soluble epoxide hydrolase (sEH) has been used in combination with cyclooxygenase (COX) inhibition or transcription factor agonism. sEH enzymes promote the hydrolysis of the AA metabolite epoxy dicarbonyl trienoic acids (EETs) to the corresponding less biologically active diols (DHETEs). By inhibiting sEH, EET levels are elevated. EET is the major eicosanoid in the human kidney and has anti-inflammatory properties. Elevated sEH expression or reduced EET levels in the kidney have been associated with hypertension, diabetes, and kidney disease. Inhibition of sEH also prevents renal inflammation and interstitial fibrosis by inhibiting the conversion of endothelial cells to mesenchymal cells and the expression of a-smooth muscle actin and TGF-b. Thus, sEH inhibition in combination with another therapeutic target could treat hypertension or diabetes while fighting renal disease.
Standardized Cistanche
The Effectiveness of Cistanche on the Health Management of Kidney Transplantation
One of the biggest challenges for individuals who undergo kidney transplantation is the risk of rejection and infection. It is important for these patients to maintain a healthy lifestyle, including good nutrition and exercise, to support their overall immune function and aid in the prevention of complications post-surgery. Cistanche, a traditional Chinese herb, has been studied for its potential health benefits and its effectiveness in supporting kidney health.
Studies have shown that Cistanche can increase antioxidant capacity and reduce oxidative stress in the body, leading to improved kidney function. Additionally, Cistanche has been found to have anti-inflammatory properties, which may help to prevent tissue damage and promote healing after kidney transplantation surgery.
One study conducted on kidney transplant recipients found that those who took Cistanche supplements had significantly lower levels of creatinine and blood urea nitrogen (BUN), indicating improved kidney function. They also experienced fewer infections compared to the control group that did not take the supplement.
However, it is important to note that more research is needed to fully understand the effectiveness and safety of Cistanche as a supplement for kidney transplantation patients. As with any supplement, it is recommended that individuals consult with their healthcare provider before adding Cistanche or any other herbal supplement to their routine.
In conclusion, Cistanche may hold promise as a natural supplement to support the health management of kidney transplantation patients. More research is needed to fully understand its effectiveness and potential risks, but initial studies suggest that it is worth considering as part of a comprehensive approach to maintaining kidney health.
References
1. Foley RN, Collins AJ: End-stage renal disease in the United States: An update from the United States renal data system. J Am Soc Nephrol 18: 2644–2648, 2007
2. US Department for Health and Human Services Centers for Disease Control and Prevention: Chronic Kidney Disease in the United States, 2019.
3. National Kidney Foundation: Chronic kidney disease (CKD) symptoms and causes, 2017. Available at:
4. Loftus TJ, Filiberto AC, Ozrazgat-Baslanti T, Gopal S, Bihorac A: Cardiovascular and renal disease in chronic critical illness. J Clin Med 10: 1601, 2021
5. Scholz H, Boivin FJ, Schmidt-Ott KM, Bachmann S, Eckardt KU, Scholl UI, Persson PB: Kidney physiology and susceptibility to acute kidney injury: Implications for renoprotection. Nat Rev Nephrol 17: 335–349, 2021
6. Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, Kellum JA, Ronco C; ADQI XIII Work Group: Progression after AKI: Understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol 27: 687–697, 2016
7. Basile DP, Anderson MD, Sutton TA: Pathophysiology of acute kidney injury. Compr Physiol 2: 1303–1353, 2012
8. D’Agati VD, Chagnac A, de Vries APJ, Levi M, Porrini E, Herman-Edelstein M, Praga M: Obesity-related glomerulopathy: Clinical and pathologic characteristics and pathogenesis. Nat Rev Nephrol 12: 453–471, 2016
9. Zoja C, Xinaris C, Macconi D: Diabetic nephropathy: Novel molecular mechanisms and therapeutic targets. Front Pharmacol 11: 586892, 2020
10. Floege J, Barbour SJ, Cattran DC, Hogan JJ, Nachman PH, Tang SCW, Wetzels JFM, Cheung M, Wheeler DC, Winkelmayer WC, Rovin BH, Adler SG, Alpers CE, Ayoub I, Bagga A, Barratt J, Caster DJ, Chan DTM, Chang A, Choo JCJ, Cook HT, Coppo R, Fervenza FC, Fogo AB, Fox JG, Gibson KL, Glassock RJ, Harris D, Hodson EM, Hoxha E, Iseki K, Jennette JC, Jha V, Johnson DW, Kaname S, Katafuchi R, Kitching AR, Lafayette RA, Li PKT, Liew A, Lv J, Malvar A, Maruyama S, Mejıa-Vilet JM, Moeller MJ, Mok CC, Nester CM, Noiri E, O'Shaughnessy MM, € Ozen S, Parikh SM, Park H-C, Peh CA, Pendergraft WF, Pickering MC, Pillebout E, Radhakrishnan J, Rathi M, Roccatello D, Ronco P, Smoyer WE, Tesar V, Thurman JM, Trimarchi H, Vivarelli M, Walters GD, Wang AY-M, Wenderfer SE; for Conference Participants: Management and treatment of glomerular diseases (part 1): Conclusions from a kidney disease: Improving global outcomes (KDIGO) controversies conference. Kidney Int 95: 268–280, 2019
11. Rovin BH, Caster DJ, Cattran DC, Gibson KL, Hogan JJ, Moeller MJ, Roccatello D, Cheung M, Wheeler DC, Winkelmayer WC, Floege J, Adler SG, Alpers CE, Ayoub I, Bagga A, Barbour SJ, Barratt J, Chan DTM, Chang A, Choo JCJ, Cook HT, Coppo R, Fervenza FC, Fogo AB, Fox JG, Glassock RJ, Harris D, Hodson EM, Hogan JJ, Hoxha E, Iseki K, Jennette JC, Jha V, Johnson DW, Kaname S, Katafuchi R, Kitching AR, Lafayette RA, Li PKT, Liew A, Lv J, Malvar A, Maruyama S, Mejıa-Vilet JM, Mok CC, Nachman PH, Nester CM, Noiri E, O'Shaughnessy MM, € Ozen S, Parikh SM, Park H-C, Peh CA, Pendergraft WF, Pickering MC, Pillebout E, Radhakrishnan J, Rathi M, Ronco P, Smoyer WE, Tang SCW, Tesar V, Thurman JM, Trimarchi H, Vivarelli M, Walters GD, Wang AY-M, Wenderfer SE, Wetzels JFM; Conference Participants: Management and treatment of glomerular diseases (part 2): Conclusions from a kidney disease: Improving global outcomes (KDIGO) controversies conference. Kidney Int 95: 281–295, 2019
12. Holdsworth SR, Gan PY, Kitching AR: Biologics for the treatment of autoimmune renal diseases. Nat Rev Nephrol 12: 217– 231, 2016
13. Meng XM, Nikolic-Paterson DJ, Lan HY: Inflammatory processes in renal fibrosis. Nat Rev Nephrol 10: 493–503, 2014
14. Proschak E, Stark H, Merk D: Polypharmacology by design: A medicinal chemist’s perspective on multitargeting compounds. J Med Chem 62: 420–444, 2019
15. Bansal Y, Silakari O: Multifunctional compounds: Smart molecules for multifactorial diseases. Eur J Med Chem 76: 31–42, 2014
16. Talevi A: Multi-target pharmacology: Possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front Pharmacol 6: 205, 2015
17. Chalikias G, Tziakas D: Angiotensin receptor neprilysin inhibitors-2019 update. Cardiovasc Drugs Ther 34: 707–722, 2020
18. Gori M, D’Elia E, Senni M: Sacubitril/valsartan therapeutic strategy in HFpEF: Clinical insights and perspectives. Int J Cardiol 281: 158–165, 2019
19. Imig JD: Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics. Pharmacol Ther 192: 1–19, 2018
20. Libby AE, Jones B, Lopez-Santiago I, Rowland E, Levi M: Nuclear receptors in the kidney during health and disease. Mol Aspects Med 78: 100935, 2021
John D. Imig 1 , Daniel Merk 2 and Eugen Proschak2
1 Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
