Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques

Gillis, Richard B.; Solomon, H.V.; Govada, Lata; Oldham, Neil J.; Dinu, Vlad; Jiwani, Shahwar I.; Gyasi-Antwi, Philemon; Coffey, Frank; Meal, Andy; Morgan, Paul S.; Harding, Stephen E.; Helliwell, John R.; Chayen, Naomi E.; Adams, Gary G.

doi:10.1038/s41598-021-81251-2

Cited by 10 publications

(5 citation statements)

References 23 publications

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“…This diversity is important to assess how generally effective the nucleants are, or whether their efficacy may correlate with protein size or charge. Glulisine and alpha‐crustacyanin are actively pursued target proteins, the structure of the former having been published only recently; [ 25 ] a high‐resolution structure of the complete alpha‐crustacyanin has not yet been determined. The other proteins, in this study, are regularly used as benchmarks (model proteins) for understanding crystallization and developing new methodology.…”

Section: Resultsmentioning

confidence: 99%

Graphene‐Based Nucleants for Protein Crystallization

Govada

Carrero

Saridakis

et al. 2022

Adv Funct Materials

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Protein crystallization remains a major bottleneck for the determination of high resolution structures. Nucleants can accelerate the process but should ideally be compatible with high throughput robotic screening. Polyethylene glycol grafted (PEGylated) graphenes can be stabilized in water providing dispensable, nucleant systems. Two graphitic feedstocks are exfoliated and functionalized with PEG using a non-destructive, scalable, chemical reduction method, delivering good water dispersibility (80 and 750 µg mL −1 for large and small layers, respectively). The wide utility of these nucleants has been established across five proteins and three different screens, each of 96 conditions, demonstrating greater effectiveness of the dispersed PEGylated graphenes. Smaller numbers of larger, more crystalline flakes consistently act as better protein nucleants. The delivered nucleant concentration is optimized (0.1 mg mL −1 in the condition), and the performance benchmarked against existing state of the art, molecularly imprinted polymer nucleants. Strikingly, graphene nucleants are effective even when decreasing both the nucleant and protein concentration to unusually low concentrations. The set-up to scale-up nucleant production to liter volumes can provide sufficient material for wide implementation. Together with the optimized crystallization conditions, the results are a step forward toward practical synthesis of a readily accessible "universal" nucleant.

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Section: Resultsmentioning

confidence: 99%

Graphene‐Based Nucleants for Protein Crystallization

Govada

Carrero

Saridakis

et al. 2022

Adv Funct Materials

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“…Remarkably, though not expectedly, patient's blood glucose control proved difficult, as increasingly higher doses of insulin had to be administered in other to achieve adequate control. Patient had to be switched from a biphasic insulin regimen, using pre-mixed insulin, to a basal-bolus insulin intensification regimen [18], using the once-daily long-acting insulin glargine (Lantus), together with multiple dosages of the insulin analogue -glulisine (Apidra), a zincfree rapid-acting injectable insulin analogue with a faster onset of action than the human insulin [19]. Several studies have suggested multiple complex mechanisms through which COVID-19 disease causes dysregulation of glycemic control, ranging from a direct destructive effect of the SARS-CoV-2 on pancreatic islet beta cells through the ACE2 protein; the liberal use of glucocorticoids for the containment of the envisaged cytokine storm; to an eventual beta cell apoptosis, leading to a blunted pancreatic insulin release [17,20,21].…”

Section: Discussionmentioning

confidence: 99%

Lessons Learnt from the Management of Severe COVID-19 Disease in a 93-year-old with Chronic Co-Morbidities at a Resource-constrained Centre in Nigeria – A Retrospective Single Case Study

Nwatu

Anyim

Unigwe

2023

IJTDH

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Introduction: Severe COVID-19 infection is associated with significant mortality in the elderly. This is even more so, when the elderly patient with the disease also has multiple chronic co-morbidities, and is resident in a resource-constrained area. Aims/ Objectives: To outline management strategies employed, and important lessons learnt from the successful management of a case of severe COVID-19 disease in a 93-year-old with chronic co-morbidities in a resource-limited setting. Methods: We utilized a simple COVID-19 severity categorization algorithm on presentation, to assign the index patient to the appropriate COVID-19 disease severity class and subsequently employed patient’s serial, weekly clinical and laboratory parameters to guide a multi-specialty management protocol. Results: A 93-year-old man was referred to a tertiary hospital in Enugu during the second wave of the COVID-19 pandemic, with a 5-day-history of high grade fever, severe fatigue, and altered sensorium. He had been living with diabetes for 48years; recently had worsening glycemic control, and was yet to pass urine in the previous 12hours. He was also being managed conservatively for prostate carcinoma. Examination revealed signs of severe pneumonia and he was drowsy, dehydrated, and had asterixis. A diagnosis of acute kidney injury from septicemia, following community acquired pneumonia and possibly urinary tract infection was made, with COVID-19 infection as a differential. Samples were collected for laboratory investigations while he was recommended for intensive care unit admission for further care. Para-enteral broad spectrum antibiotics, intravenous fluid therapy, intranasal oxygen therapy, basal-bolus-insulin-regimen, and anti-coagulation prophylaxis were instituted. Following laboratory investigation results which included a positive COVID-19 test (clinically categorized as severe disease), severe systemic inflammation, evidence of uro-tract infection, intravascular thrombosis and severe renal impairment, the Nephrology, Infectious disease, Urology teams were invited to co-manage the patient alongside the Endocrinologists. After 27days of collaborative care, patient was discharged with resolution of his symptoms and signs. Conclusion: Multi-specialty collaborative care improves patients’ outcome even in the face of severe COVID-19 with associated co-morbidities in elderly patients. Severity stratification ensures life-saving timely care for severe COVID-19 disease.

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“…La insulina aspart 27 (introducida en el año 2000) tiene una acción prácticamente idéntica a la lis-pro, debida a la sustitución de aspártico en vez de prolina en la posición 28 de la cadena B. La insulina glulisina 28 (introducida en 2006) difiere de la insulina humana por el reemplazo de dos aminoácidos: lisina, en sustitución de asparagina en la posición 3, y ácido glutámico, en sustitución de lisina en la posición 29, ambos en la cadena B. Como en el caso de la lis-pro, estos cambios permiten una asociación intermolecular disminuida entre las cadenas B. Esta estructura y la interacción de las cadenas B se ha confirmado recientemente con repulsión electrostática entre las cadenas B resultantes de las modificaciones mencionadas 29 .…”

Section: Análogos De Acción Rápidaunclassified