Michael A. Weiss
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View article: Ultrastable Insulin-Glucagon Fusion Protein Exploits an Endogenous Hepatic Switch to Mitigate Hypoglycemic Risk
Ultrastable Insulin-Glucagon Fusion Protein Exploits an Endogenous Hepatic Switch to Mitigate Hypoglycemic Risk Open
The risk of hypoglycemia and its serious medical sequelae restrict insulin replacement therapy for diabetes mellitus. Such adverse clinical impact has motivated development of diverse glucose-responsive technologies, including algorithm-co…
View article: Evolution of the Artificial Pancreas: Components and Integration—CGMs, Insulin, and AP Systems
Evolution of the Artificial Pancreas: Components and Integration—CGMs, Insulin, and AP Systems Open
The landmark Diabetes Control and Complications Trial (DCCT) showed that glucose control is critical to reducing the risk of diabetes-related complications. This chapter outlines a series of innovations and investigations that followed the…
View article: Stabilization of a protein by a single halogen‐based aromatic amplifier
Stabilization of a protein by a single halogen‐based aromatic amplifier Open
The utility of halogenation in protein design is investigated by a combination of quantitative atomistic simulations and experiment. Application to insulin is of complementary basic and translational interest. In a singly halogenated aroma…
View article: 12554 Human Sex Determination: SRY Length Regulates Its Cellular Stability And Hence The Robustness Of Testis Differentiation
12554 Human Sex Determination: SRY Length Regulates Its Cellular Stability And Hence The Robustness Of Testis Differentiation Open
Disclosure: M.A. Weiss: None. SRY length regulates its cellular stability and hence the robustness of testis determinationYen-Shan Chen[1], Ella Thomson2, Emanuele Pelosi[1], & Michael A. Weiss[1]*[1]Department of Biochemistry & Molecular …
View article: 12554 Human Sex Determination: SRY Length Regulates Its Cellular Stability And Hence The Robustness Of Testis Differentiation
12554 Human Sex Determination: SRY Length Regulates Its Cellular Stability And Hence The Robustness Of Testis Differentiation Open
Disclosure: M.A. Weiss: None. The abundance of transcription factors (TFs) mediated by the rates of degradation are subjected to be a robust to an appropriate level. This regulation via the proteasome is largely controlled by the stability…
View article: Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk
Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk Open
The risk of hypoglycemia and its serious medical sequelae restrict insulin replacement therapy for diabetes mellitus. Such adverse clinical impact has motivated development of diverse glucose-responsive technologies, including algorithm-co…
View article: Se‐Glargine: Chemical Synthesis of a Basal Insulin Analogue Stabilized by an Internal Diselenide Bridge
Se‐Glargine: Chemical Synthesis of a Basal Insulin Analogue Stabilized by an Internal Diselenide Bridge Open
Insulin has long provided a model for studies of protein folding and stability, enabling enhanced treatment of diabetes mellitus via analogue design. We describe the chemical synthesis of a basal insulin analogue stabilized by substitution…
View article: In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins
In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins Open
The glucose-responsive insulin (GRI) MK-2640 from Merck was a pioneer in its class to enter the clinical stage, having demonstrated promising responsiveness in in vitro and preclinical studies via a novel competitive clearance mechanism (C…
View article: Se-Glargine I. Chemical Synthesis of a Basal Insulin Analog Stabilized by an Internal Diselenide Bridge
Se-Glargine I. Chemical Synthesis of a Basal Insulin Analog Stabilized by an Internal Diselenide Bridge Open
Insulin, a small globular protein, has long provided a model for studies of biophysical principles with therapeutic application. The safety and efficacy of insulin replacement therapy for the treatment for diabetes mellitus have been enhan…
View article: Se-Glargine II. Native Function of a Basal Insulin Analog Stabilized by an Internal Diselenide Bridge
Se-Glargine II. Native Function of a Basal Insulin Analog Stabilized by an Internal Diselenide Bridge Open
Insulin glargine, the active component of basal clinical pharmaceutical formulations Lantus® and Toujeo® (Sanofi), provides a model for principles of therapeutic protein design. Formulated in solution at pH 4, insulin glargine exhibits a s…
View article: Rational Design and Efficacy of Glucose‐Responsive Insulin Therapeutics and Insulin Delivery Systems by Computation Using Connected Human and Rodent Models
Rational Design and Efficacy of Glucose‐Responsive Insulin Therapeutics and Insulin Delivery Systems by Computation Using Connected Human and Rodent Models Open
Glucose‐responsive insulins (GRIs) use plasma glucose levels in a diabetic patient to activate a specifically designed insulin analogue to a more potent state in real time. Alternatively, some GRI concepts use glucose‐mediated release or i…
View article: Acute disseminated encephalomyelitis (ADEM)-like illness in a pediatric patient following COVID-19 vaccination
Acute disseminated encephalomyelitis (ADEM)-like illness in a pediatric patient following COVID-19 vaccination Open
Since the inception of the COVID-19 pandemic, over 60 cases of acute disseminated encephalomyelitis (ADEM) or ADEM-like clinically isolated syndromes have been linked to COVID-19 infection. However, cases linked to COVID-19 vaccination rem…
View article: Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity
Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity Open
Y-encoded transcription factor SRY initiates male differentiation in therian mammals. This factor contains a high-mobility-group (HMG) box, which mediates sequence-specific DNA binding with sharp DNA bending. A companion article in this is…
View article: RF04 | PSUN233 Design of an Ultra-Stable Insulin/Glucagon Fusion Protein
RF04 | PSUN233 Design of an Ultra-Stable Insulin/Glucagon Fusion Protein Open
Insulin replacement therapy is lifesaving for insulin-dependent diabetic patients, but it comes with an ever-present threat of hypoglycemia, which can eventually cause ischemic events, arrhythmias, neurological damage, coma, or even death.…
View article: 1194 Discovery and pre-clinical development of a novel and differentiated EphA2-targeted antibody in multiple bispecific formats
1194 Discovery and pre-clinical development of a novel and differentiated EphA2-targeted antibody in multiple bispecific formats Open
Background Eph proteins are the largest family of receptor tyrosine kinases in humans and are normally involved in cell-to-cell communication, plasticity, and patterning. EphA2 represents an attractive therapeutic target due to its overexp…
View article: Tenuous Transcriptional Threshold of Human Sex Determination. I. SRY and Swyer Syndrome at the Edge of Ambiguity
Tenuous Transcriptional Threshold of Human Sex Determination. I. SRY and Swyer Syndrome at the Edge of Ambiguity Open
Male sex determination in mammals is initiated by SRY, a Y-encoded transcription factor. The protein contains a high-mobility-group (HMG) box mediating sequence-specific DNA bending. Mutations causing XY gonadal dysgenesis (Swyer syndrome)…
View article: Stabilization of a Protein by a Single Halogen-Based Aromatic Amplifier
Stabilization of a Protein by a Single Halogen-Based Aromatic Amplifier Open
The utility of halogenation in protein design is investigated by a combination of quantitative atomistic simulations and experiment. The approach is applied to insulin, a small, therapeutically relevant domain amenable to simulation and se…
View article: Beyond the trauma hero: the discourse of American war fiction from the Global War on Terror
Beyond the trauma hero: the discourse of American war fiction from the Global War on Terror Open
The recent US troop withdrawal from Afghanistan, the last major theatre of war for post 9/11 veterans, marks a turning point for the United States. This new period of relative warlessness allows the nation to reflect on its collective expe…
View article: Peptide Model of the Mutant Proinsulin Syndrome. I. Design and Clinical Correlation
Peptide Model of the Mutant Proinsulin Syndrome. I. Design and Clinical Correlation Open
The mutant proinsulin syndrome is a monogenic cause of diabetes mellitus due to toxic misfolding of insulin’s biosynthetic precursor. Also designated mutant INS-gene induced diabetes of the young (MIDY), this syndrome defines molecular det…
View article: Peptide Model of the Mutant Proinsulin Syndrome. II. Nascent Structure and Biological Implications
Peptide Model of the Mutant Proinsulin Syndrome. II. Nascent Structure and Biological Implications Open
Toxic misfolding of proinsulin variants in β-cells defines a monogenic diabetes syndrome, designated mutant INS-gene induced diabetes of the young (MIDY). In our first study (previous article in this issue), we described a one-disulfide pe…
View article: Generation and mutational analysis of a transgenic mouse model of human <i>SRY</i>
Generation and mutational analysis of a transgenic mouse model of human <i>SRY</i> Open
SRY is the Y-chromosomal gene that determines male sex development in humans and most other mammals. After three decades of study, we still lack a detailed understanding of which domains of the SRY protein are required to engage the pathwa…
View article: New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals
New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals Open
Design of “first-generation” insulin analogues over the past 3 decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool kit—integrating protein…
View article: Structural Lessons From the Mutant Proinsulin Syndrome
Structural Lessons From the Mutant Proinsulin Syndrome Open
Insight into folding mechanisms of proinsulin has been provided by analysis of dominant diabetes-associated mutations in the human insulin gene ( INS ). Such mutations cause pancreatic β-cell dysfunction due to toxic misfolding of a mutant…
View article: Age of diabetes onset in the mutant proinsulin syndrome correlates with mutational impairment of protein foldability and stability
Age of diabetes onset in the mutant proinsulin syndrome correlates with mutational impairment of protein foldability and stability Open
Diverse heterozygous mutations in the human insulin gene cause a monogenic diabetes mellitus (DM) syndrome due to toxic misfolding of the variant proinsulin. Whereas mutations that add or remove cysteines (thereby leading to an odd number …
View article: Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial
Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial Open
Federal Ministry of education and research (BMBF; Project B-FAST in "NaFoUniMedCovid19"; registration number: 01KX2021).
View article: Structural principles of insulin formulation and analog design: A century of innovation
Structural principles of insulin formulation and analog design: A century of innovation Open
Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever m…