Drug Delivery Strategies for Enhancing the Therapeutic Efficacy of Toxin-Derived Anti-Diabetic Peptides

toxins Review Drug Delivery Strategies for Enhancing the Therapeutic Efficacy of Toxin-Derived Anti-Diabetic Peptides Reeju Amatya 1 , Taehoon Park 1 , Seungmi Hwang 2 , JaeWook Yang 3,4 , Yoonjin Lee 4 , Heesun Cheong 5 , Cheol Moon 6 , Hyun Duck Kwak 3 , Kyoung Ah Min 2, * and Meong Cheol Shin 1, * 1 2 3 4 5 6 * College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju, Gyeongnam 52828, Korea; (R.A.); (T.P.) College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae, Gyeongnam 50834, Korea; Department of Ophthalmology, Busan Paik Hospital, Inje University College of Medicine, 75 Bokjiro, Busanjin-gu, Busan 47392, Korea; (J.Y.); (H.D.K.) T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, 81 Jinsaro 83 Beon-gil, Busanjin-gu, Busan 47397, Korea; Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 10408, Korea; College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon, Jeonnam 57922, Korea; Correspondence: (K.A.M.); (M.C.S.); Tel.: +82-55-320-3459 (K.A.M.); +82-55-772-2429 (M.C.S.) Received: 10 April 2020; Accepted: 6 May 2020; Published: 10 May 2020



 Abstract: Toxin peptides derived from the skin secretions of amphibians possess unique hypoglycemic activities. Many of these peptides share cationic and amphipathic structural similarities and appear to possess cell-penetrating abilities. The mechanism of their insulinotropic action is yet not elucidated, but they have shown great potential in regulating the blood glucose levels in animal models. Therefore, they have emerged as potential drug candidates as therapeutics for type 2 diabetes. Despite their anti-diabetic activity, there remain pharmaceutical challenges to be addressed for their clinical applications. Here, we present an overview of recent studies related to the toxin-derived anti-diabetic peptides derived from the skin secretions of amphibians. In the latter part, we introduce the bottleneck challenges for their delivery in vivo and general drug delivery strategies that may be applicable to extend their blood circulation time. We focus our research on the strategies that have been successfully applied to improve the plasma half-life of exendin-4, a clinically available toxin-derived anti-diabetic peptide drug. Keywords: toxin; diabetes; anti-diabetic peptide; drug delivery; plasma half-life; cell-penetrating peptide Key Contribution: This review provides recently updated information about anti-diabetic peptides derived from skin secretions of amphibians with cell-penetrating activities and drug delivery strategies applicable to extend their blood circulation time. 1. Introduction Diabetes is a metabolic disorder in which the blood glucose level is not orderly regulated and maintains a higher-than-normal level. Specifically, type 2 diabetes mellitus (T2DM), the most prevalent Toxins 2020, 12, 313; doi:10.3390/toxins12050313 www.mdpi.com/journal/toxins Toxins 2020, 12, 313 2 of 18 type of diabetes, is heavily related to obesity, a prevalent condition in the modern lifestyle [1]. T2DM is characterized by high blood glucose levels, insulin resistance, and progressively reducing plasma insulin levels [2]. The conventional therapeutics for the T2DM usually work by inhibiting the glucose production in the liver, sensitizing the insulin receptors, and enhancing insulin secretion [3]. At the later stage of T2DM, when eventually the pancreatic beta cells become deteriorated and unable to produce sufficient insulin, treatment of exogenous insulin is necessary [4]. Considering the life-threatening complications of diabetes and the inability of current therapies to completely resolve the diabetic conditions, there has continuously been a need to discover a novel therapeutic agent [5]. To date, natural and synthetic peptides which are biological active are gaining great attention as potential drug candidates [6–9]. Compared with small molecule-based drugs, these therapeutic peptides are usually considered more potent and specific, but less toxic [10]. Moreover, thanks to advances in techniques for peptide synthesis, screening, and analysis, the industrialization of peptide drugs has become more feasible. In this context, exendin-4 (tradename: Byetta; Amylin Pharmaceuticals, Inc.), was approved by the FDA in 2005 as the first toxin-derived peptide therapeutic for the treatment of T2DM [11]. Exendin-4, a 39-mer peptide, was first identified in the salivary secretions of a venomous lizard species known as the Gila monster, Heloderma suspectum [11]. The exendin-4 has a 53% structural similarity to the GLP-1 (Glucagon-like protein-1) and possesses anti-diabetic activity [11]. One of the major advantages of exendin-4 over the endogenous GLP-1 is its great stability against the dipeptidyl peptidase-4 (DPP-4) enzyme that enables much longer action in the body [12,13]. However, the plasma half-life of exendin-4 is still relatively short (2.4 h) and thus requires twice-daily injections for adequate hypoglycemic control. To reduce the frequency of the injection and improve the patients’ compliance, an extensive amount of research has been conducted to develop effective ways to prolong the plasma half-life of exendin-4 and, indeed, some of those exendin-4 analogs are clinically available [14–17]. Following the success of exendin-4, many peptides with potent anti-diabetic activities have been discovered from various animal sources including cone snails [18], reptiles [19], and amphibians [20]. These peptides could stimulate insulin release from beta cells and lower blood glucose levels in animals. Their mechanism for the insulinotropic activities varies depending on the peptide. While the exendin-4 and the insulin toxin of cone snails elicit insulin release by binding to their specific receptors (GLP-1R and insulin receptor, respectively), various snake venoms directly act on channels that play major roles in insulin secretion [18–20]. However, for the toxin-derived anti-diabetic peptides derived from the skin secretions of amphibians, their molecular targets are not yet clear. To date, a large group of toxin-derived anti-diabetic peptides have been discovered from the skin secretions of amphibians and their activities have been assessed. Recently, more and more studies have been focused on the modification of the peptide sequences and structures to reduce their intrinsic toxicities and improve glucoregulatory efficacy. However, due to drug delivery challenges, many studies are limited to cellular levels and a systemic characterization of their activities in animal models is as yet insufficient. This review will introduce toxin-derived anti-diabetic peptides focused on the peptides derived from the skin secretions of amphibians that possess cell-penetrating ability. After that, (...truncated)