REPURPOSING AND MORPHING: A COMBINED STRATEGY TO DESIGN MULTI TARGET LIGANDS

Type 2 diabetes mellitus (T2DM) is one of the priority global health problems, which is characterized by dysregulation of carbohydrate, lipid, and protein metabolism and results from impaired insulin secretion, insulin resistance, or a combination of both. The global burden of diabetes had increased significantly since 19901, compelled to face this syndrome not only as a major threat to public health but also to socio-economic development. The explosion of T2DM prevalence over the past half-century has paralleled that of the obesity epidemic2. The two inflammatory diseases are correlated since it has been shown that obesity induces immune cell changes in adipose tissue that affect insulin sensitivity3,4. Obesity and insulin resistance are two key drivers in the development of T2DM and are also connected to the development of both microvascular complications (including retinopathy, nephropathy, and neuropathy) and macrovascular complications (such as cardiovascular comorbidities). Other notable risk factors include a poor diet, low physical activity levels, and older age. Multifactorial risk reduction strategies to normalize blood levels, lipid profile, and blood pressure are required to manage T2DM. Furthermore, it is also required continuous medical care, patient self-management for control of abnormal glucose levels. Achievement of glycemic control requires a pharmacological approach that has progressed from biguanides and metformin to a wide spectrum of medications that seems to provide a beneficial effect on morbidity and mortality. Despite this, the target treatment goals are still not completely reached, so polypharmacological treatment is needed5. However, complex treatment regimens may lead to drug-drug interaction and/or poor patient adherence. Thus, novel antidiabetic drug classes capable of acting on several levels simultaneously are required. Nevertheless, in the state of metabolic disturbance, several major enzymes are abnormally expressed, thus they could be interesting targets in drug development. Hence, again, multimodal drugs, which could reduce hyperglycemia and concomitantly inhibit the progression of complications, may offer a valuable therapeutic option. The design of these multi-target ligands must focus on the selection of suitable targets, which must be well characterized and preferably implicated in different pathways of the disease, and on the optimization of the relative potency of the compound towards each interested protein6. To find new therapeutic compounds, a repurposing approach was applied on WB-4101, a well-known adrenergic ligand, to obtain potential dual ligands that would target different enzymes involved in T2DM, namely Dipeptidyl Peptidase IV (DPP-IV) and Carbonic Anhydrase (CA-II and V). DPP-IV inhibitors prolong the half-life of the glucose-dependent insulinotropic polypeptide hormone (GIP) and the glucagon-like peptide 1 (GLP-1), two important regulators of post-prandial glycemic control7. On the other hand, CA inhibitors could be useful in the prevention of several common diabetic comorbidities. WB-4101 has been chosen as a good “repurposable” candidate since previous computational studies showed that it conveniently fits into all these enzymes’ pockets even if fails to interact with some key residues. To strengthen interactions towards the target enzymes, morphing WB-4101 has been required. Furthermore, this approach can lead to the design of more “drug-like” compounds with low molecular weight and with respect to Lipinski's rule of five. Moreover, morphing would allow the modulation of the activity toward the old and new targets. References 1. Saeedi, P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 157, (2019). 2. Wang, Y. C., McPherson, K., Marsh, T., Gortmaker, S. L. & Brown, M. Health and economic burden of the projected obesity trends in the USA and the UK. The Lancet vol. 378 815–825 (2011). 3. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003). 4. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003). 5. Artasensi, A., Pedretti, A., Vistoli, G. & Fumagalli, L. Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs. Molecules 25, 1987 (2020). 6. Morphy, R., Kay, C. & Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today 9, 641–651 (2004). 7. Irwin, N. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J. Diabetes 6, 1285 (2015).