Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells

Lee, Miseon; Maji, Basudeb; Manna, Debasish; Kahraman, Sevim; Elgamal, Ruth M.; Small, Jonnell; Kokkonda, Praveen; Vetere, Amedeo; Goldberg, Jacob M.; Lippard, Stephen J.; Kulkarni, Rohit; Wagner, Bridget K.; Choudhary, Amit

doi:10.1021/jacs.0c00099

Cited by 25 publications

(34 citation statements)

References 37 publications

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“…3B). Previously, we and other groups also characterized zincchelating ligands for imaging and proliferation purposes and reported the kinetics of zinccatalyzed hydrolysis in multiple ZnPD systems, both biochemically and in  cells (34). In all of these systems, kinetics of release of our ZnPDs were monitored and release was shown to occur within one hour in  cells, similar to what has been reported by Lippard and coworkers (35).…”

Section: Zinc-binding Scaffold For  Cell-specific Delivery Of Harminesupporting

confidence: 75%

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells

et al. 2020

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Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in β cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)—a high-fidelity culture system where stem cell–derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation—so preferentially in β cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in β cell proliferation compared to harmine.

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Section: Zinc-binding Scaffold For  Cell-specific Delivery Of Harminesupporting

confidence: 75%

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells

et al. 2020

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“…Other possibilities exist as well. Annes et al and Choudhary et al have taken advantage of the presence of zinc transporters such as ZnT8 encoded by the SLC30A8 gene that allow beta cells to package insulin in dense core secretory granules, comprised of hexameric insulin crystals, the formation of which requires zinc ion (124,125). Insulin packaging into dense core secretory granules requires crystallization of insulin hexamers.…”

Section: Is Beta Cell Targeting Necessary or Possible?mentioning

confidence: 99%

“…Annes et al used a zinc-chelator, DPA, to transport GNF4877 into the mouse and human beta cell in a specific manner (124). Choudhary et al developed a zinc chelator, ZnPD5, bearing GNF4877, as a zinc-sensitive prodrug, able to selectively release GNF4877 in the interior of beta cells (125). How these stories unfold in the upcoming months and years will be of great interest.…”

Section: Is Beta Cell Targeting Necessary or Possible?mentioning

confidence: 99%

Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges

et al. 2021

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A quantitative deficiency of normally functioning insulin-producing pancreatic beta cells is a major contributor to all common forms of diabetes. This is the underlying premise for attempts to replace beta cells in people with diabetes by pancreas transplantation, pancreatic islet transplantation, and transplantation of beta cells or pancreatic islets derived from human stem cells. While progress is rapid and impressive in the beta cell replacement field, these approaches are expensive, and for transplant approaches, limited by donor organ availability. For these reasons, beta cell replacement will not likely become available to the hundreds of millions of people around the world with diabetes. Since the large majority of people with diabetes have some residual beta cells in their pancreata, an alternate approach to reversing diabetes would be developing pharmacologic approaches to induce these residual beta cells to regenerate and expand in a way that also permits normal function. Unfortunately, despite the broad availability of multiple classes of diabetes drugs in the current diabetes armamentarium, none has the ability to induce regeneration or expansion of human beta cells. Development of such drugs would be transformative for diabetes care around the world. This picture has begun to change. Over the past half-decade, a novel class of beta cell regenerative small molecules has emerged: the DYRK1A inhibitors. Their emergence has tremendous potential, but many areas of uncertainty and challenge remain. In this review, we summarize the accomplishments in the world of beta cell regenerative drug development and summarize areas in which most experts would agree. We also outline and summarize areas of disagreement or lack of unanimity, of controversy in the field, of obstacles to beta cell regeneration, and of challenges that will need to be overcome in order to establish human beta cell regenerative drug therapeutics as a clinically viable class of diabetes drugs.

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“…Such an approach was applied for the targeted release of fluorochromes and β-cell mitogenic compounds in human β-cells. 292 In both cases, the hybrid compounds preferentially accumulated within β-cells. Upon reaching the Zn(II)-abundant environment, the bond between the cargo and the Zn(II)-binding scaffold was cleaved, releasing the active cargo.…”

Section: Recent Strategies For Selective Targeting Of Inhibitors To Diabetes-affected Organsmentioning

confidence: 99%

“…Because of the above features, many attempts were reported to design a system for imaging β-cells. 292 …”

Section: Recent Strategies For Selective Targeting Of Inhibitors To Diabetes-affected Organsmentioning

confidence: 99%

Targeting Small GTPases and Their Prenylation in Diabetes Mellitus

2021

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A fundamental role of pancreatic β-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein–protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Hyperglycemia-induced upregulation of small GTPases suggests that inhibition of these pathways deserves to be considered as a potential therapeutic approach in treating T2D. This Perspective presents how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of diabetes-affected tissues and contribute to chronic inflammation involved in diabetes mellitus (T2D) development. We also demonstrate the currently available molecular tools to decipher the mechanisms linking the mevalonate pathway’s enzymes and GTPases with diabetes.

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Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells

Cited by 25 publications

References 37 publications

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells

Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges

Targeting Small GTPases and Their Prenylation in Diabetes Mellitus

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