Natural Α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: a Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs
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molecules Review Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs Massimo Genovese , Ilaria Nesi , Anna Caselli and Paolo Paoli * Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; [email protected] (M.G.); [email protected] (I.N.); anna.caselli@unifi.it (A.C.) * Correspondence: paolo.paoli@unifi.it; Tel.: +39-055-2751248 Abstract: Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D. Citation: Genovese, M.; Nesi, I.; Keywords: PTP1B; α-glucosidase; insulin signaling; drug discovery; type 2 diabetes Caselli, A.; Paoli, P. Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of 1. Introduction New Multitarget Antidiabetic Drugs. Molecules 2021, 26, 4818. https:// Type 2 diabetes is a complex pathology characterized by hyperglycemia and metabolic doi.org/10.3390/molecules26164818 abnormalities affecting different organs and tissues, such as liver, muscle, adipose tissue, and pancreas. To date, subjects affected by T2D can rely on several oral antihyperglycemic Academic Editor: Masahide drugs showing different mechanisms of action to keep glycaemia under control. These Hamaguchi drugs include: inhibitors of intestinal α-glucosidases, which delay intestinal absorption of glucose; metformin, which blocks hepatic gluconeogenesis; different types of secretagogues Received: 27 May 2021 that stimulate the release of insulin from pancreatic β-cells; thiazolidinediones, which Accepted: 7 August 2021 stimulate the storage of circulating fatty acids into adipocytes, thereby improving insulin Published: 9 August 2021 sensitivity in several peripheral tissues; and the sodium/glucose cotransporter 2 (SGLT-2) inhibitors, which impair the re-uptake of glucose in the renal tubules [1]. The choice Publisher’s Note: MDPI stays neutral of the most appropriate hypoglycemic drug for a patient depends on several factors, with regard to jurisdictional claims in such as the patient’s general condition, the presence of comorbidities, tolerance, and the published maps and institutional affil- patient’s response to the drug. Generally, most diabetic patients showing hyperglycemia iations. without further pathological complications respond positively to single-drug based therapy (Figure1 ), experiencing a decrease of blood sugar levels and an improvement of their general conditions. However, many clinical studies showed that benefits obtained with this approach Copyright: © 2021 by the authors. are transient, and in the medium to long term, patients experience a gradual rise in blood Licensee MDPI, Basel, Switzerland. sugar and a worsening of general health conditions. In some cases, the up-scaling of drug This article is an open access article dosage can allow regaining of the glycemic target, with the hope that, at the same time, distributed under the terms and no adverse effects related to high doses of the drug occur [2]. The failure of mono-drug conditions of the Creative Commons therapy is mainly due to the inability of such drugs to replace physiological functions of Attribution (CC BY) license (https:// insulin. Indeed, even if these drugs are able to compensate a specific metabolic defect, they creativecommons.org/licenses/by/ unexpectedly induce severe unbalance in other metabolic pathways. 4.0/). Molecules 2021, 26, 4818. https://doi.org/10.3390/molecules26164818 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2 of 35 Molecules 2021, 26, x 2 of 35 insulin. Indeed, even if these drugs are able to compensate a specific metabolic defect, Molecules 2021, 26, 4818 insulin. Indeed, even if these drugs are able to compensate a specific metabolic defect,2 of 34 they unexpectedly induce severe unbalance in other metabolic pathways. they unexpectedly induce severe unbalance in other metabolic pathways. Figure 1. Antidiabetic strategy based on the mono-drug therapy: each antidiabetic drug is adminis- FigureFigure 1. 1. AntidiabeticAntidiabetic strategy strategy based based on on the the mono-drug mono-drug th therapy:erapy: each each antidiabetic antidiabetic drug drug is is adminis- adminis- tered alone and works on a specific target. teredtered alone alone and and works works on on a a specific specific target. target. 1.1. Combination versus Mono-Drug Therapy for Treatment ofof T2DT2D 1.1. Combination versus Mono-Drug Therapy for Treatment of T2D The combination of two or more anti-hyperglycemicanti-hyperglycemic drugs acting on different bio- The combination of two or more anti-hyperglycemic drugs acting on different bio- logical targets targets is is a a therapeutic therapeutic option option often often used used for for treatment treatment of ofdiabetic diabetic patients patients who who do logical targets is a therapeutic option often used for treatment of diabetic patients who do notdo notadequately adequately respond respond to mono-drug to mono-drug therapy therapy [3]. [From3]. From a theoretical a theoretical point point of view, of view, the not adequately respond to mono-drug therapy [3]. From a theoretical point of view, the purposethe purpose of this of this strategy strategy is to is togenerate generate a asyne synergisticrgistic effect effect by by acting acting on on different different targets purpose of this strategy is to generate a synergistic effect by acting on different targets involved directly or indirectly inin thethe controlcontrol ofof glycemiaglycemia (Figure(Figure2 2).). involved directly or indirectly in the control of glycemia (Figure 2). Figure 2. AntidiabeticAntidiabetic strategy based on combination therapy:therapy: patients are treated with two or more Figure 2. Antidiabetic strategy based on combination therapy: patients are treated with two or more antihyperglycemic oral drugs also administered atat differentdifferent timestimes ofof thethe day.day. antihyperglycemic oral drugs also administered at different times of the day. This approach aimsaims toto generategenerate aa synergisticsynergistic effect, effect, improving improving glycemic glycemic control control using using a This approach aims to generate a synergistic effect, improving glycemic control using alower lower dosage dosage of eachof each drug drug than than the dosesthe doses provided provided by mono-drug by mono-drug therapy. therapy. However, However, despite a lower dosage of each drug than the doses provided by mono-drug therapy. However, despitethe undoubted the undoubted advantages advantages of such a of pharmacological such a pharmacological approach, approach, many clinical many trials clinical revealed tri- despite the undoubted advantages of such a pharmacological approach, many clinical tri- alsthat revealed multi-drug that therapies multi-drug are therapies difficult toare manage difficult for to themanage majority for ofthe patients majority for of different patients als revealed that multi-drug therapies are difficult to manage for the majority of patients forreasons. different For example,reasons. oftenFor example, a fine adjustment often a fine of dosagesadjustment is required, of dosages or patients is required, are asked or pa- to for different reasons. For example, often a fine adjustment of dosages is required, or pa- tientstake medications are asked to at take different medications times of at the differ dayent because times of of the their day different because pharmacokinetics. of their different tientsThese are factors asked make to take it very medications difficult for at patients different to times comply of withthe day the because therapeutic of their protocol, different thus increasing the risk of not reaching the glycemic target. The consequent uncontrolled fluctua- tions in blood sugar can be deleterious, forcing patients to change treatment to avoid further complications. A practical solution to this problem may arise from taking combinations of oral hypoglycemic drugs in fixed and pre-established doses depending on the desired Molecules 2021, 26, x 3 of 35 pharmacokinetics. These factors make it very difficult for patients to comply with the ther- apeutic protocol, thus increasing the risk of not reaching the glycemic target. The conse- Molecules 2021, 26, 4818 quent uncontrolled fluctuations in blood sugar can be deleterious, forcing patients to 3 of 34 change treatment to avoid further complications. A practical solution to this problem may arise from taking combinations of oral hypoglycemic drugs in fixed and pre-established doses depending on the desired effects. This strategy reduces the complexity of therapeu- effects. This strategy reduces the complexity of therapeutic regimen