Inhibitors of aspartic proteinases and their relevance to the design of antihypertensive agents

Cooper, J.B.; Foundling, S.; Hemmings, Andrew M.; Watson, F.E.; Sibanda, B. L.; Blundell, T.L.; Jones, D.; Hallett, Allan; Atrash, Butrus; Szelke, M.

doi:10.1042/bst0150751

Cited by 7 publications

(3 citation statements)

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“…With nearly 205 000 structures deposited in the Protein Data Bank (PDB) as of April 2023, protein X-ray crystallography has become one of the most successful structural biology techniques since the first three-dimensional structure of a protein, myoglobin, was revealed. Insulin's mechanism of action 1 mass production of penicillin, 2 understanding sickle cell anemia, 3 the structure of DNA, 4 and HIV inhibitors, 5,6 are just a few of the many world-changing discoveries made possible by X-ray crystallography. 7,8 Advancements in crystallography were enabled through technological improvements in sample handling such as the use of cryoprotectant mother liquors 9 to mitigate radiation damage and produce macromolecular structures at sub-zero temperature, 10 and sealed crystal holders, oils, and humidified environments to slow down dehydration and prolong measurement times.…”

Section: Introductionmentioning

confidence: 99%

Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Doppler,

Sonker,

Egatz-Gomez

et al. 2023

Lab Chip

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Section: Introductionmentioning

confidence: 99%

Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Doppler,

Sonker,

Egatz-Gomez

et al. 2023

Lab Chip

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“…tical companies in their drug discovery. This was achieved by using emerging knowledge of the aspartic proteinase mechanism and ideas about the transition state derived from the fungal pepsins (Tickle et al, 1984;Cooper et al, 1987;Sali et al, 1989). Fig.…”

Section: From Pepsins To Renin and The Design Of Anihypertensivesmentioning

confidence: 99%

“…Early inhibitor designs focused on modelling a transitionstate analogue, maintaining the hydrogen bonds in synthetic analogues of the substrate angiotensinogen, while modifying the peptide bonds and optimizing the interactions of the synthetic side-chain equivalents, guided by the renin model. This was achieved by continuous interactions between the academic laboratory in Birkbeck with the group of Michael Szelke (Cooper et al, 1987) and the renin medicinal chemistry group at Pfizer Groton (Sali et al, 1989). Eventually, structures of renins and their complexes with substrate analogues became available (Rahuel et al, 1991;Dhanaraj et al, 1992), which allowed more reliable structure-guided discovery.…”

Section: From Pepsins To Renin and The Design Of Anihypertensivesmentioning

confidence: 99%

Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry

Blundell¹

2017

IUCrJ

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The development of structure-guided drug discovery is a story of knowledge exchange where new ideas originate from all parts of the research ecosystem. Dorothy Crowfoot Hodgkin obtained insulin from Boots Pure Drug Company in the 1930s and insulin crystallization was optimized in the company Novo in the 1950s, allowing the structure to be determined at Oxford University. The structure of renin was developed in academia, on this occasion in London, in response to a need to develop antihypertensives in pharma. The idea of a dimeric aspartic protease came from an international academic team and was discovered in HIV; it eventually led to new HIV antivirals being developed in industry. Structure-guided fragment-based discovery was developed in large pharma and biotechs, but has been exploited in academia for the development of new inhibitors targeting protein–protein interactions and also antimicrobials to combat mycobacterial infections such as tuberculosis. These observations provide a strong argument against the so-called `linear model', where ideas flow only in one direction from academic institutions to industry. Structure-guided drug discovery is a story of applications of protein crystallography and knowledge exhange between academia and industry that has led to new drug approvals for cancer and other common medical conditions by the Food and Drug Administration in the USA, as well as hope for the treatment of rare genetic diseases and infectious diseases that are a particular challenge in the developing world.

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High-resolution X-ray diffraction study of the complex between endothiapepsin and an oligopeptide inhibitor: the analysis of the inhibitor binding and description of the rigid body shift in the enzyme.

et al. 1989

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The conformation of the synthetic renin inhibitor CP‐69,799, bound to the active site of the fungal aspartic proteinase endothiapepsin (EC 3.4.23.6), has been determined by X‐ray diffraction at 1.8 A resolution and refined to the crystallographic R factor of 16%. CP‐69,799 is an oligopeptide transition‐‐state analogue inhibitor that contains a new dipeptide isostere at the P1‐P1′ position. This dipeptide isostere is a nitrogen analogue of the well‐explored hydroxyethylene dipeptide isostere, wherein the tetrahedral P1′ C alpha atom has been replaced by trigonal nitrogen. The inhibitor binds in the extended conformation, filling S4 to S3′ pockets, with hydroxyl group of the P1 residue positioned symmetrically between the two catalytic aspartates of the enzyme. Interactions between the inhibitor and the enzyme include 12 hydrogen bonds and extensive van der Waals contacts in all the pockets, except for S3′. The crystal structure reveals a bifurcated orientation of the P2 histidine side chain and an interesting relative rotation of the P3 phenyl ring to accommodate the cyclohexyl side chain at P1. The binding of the inhibitor to the enzyme, while producing no large distortions in the enzyme active site cleft, results in small but significant change in the relative orientation of the two endothiapepsin domains. This structural change may represent the action effected by the proteinase as it distorts its substrate towards the transition state for proteolytic cleavage.

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Inhibitors of aspartic proteinases and their relevance to the design of antihypertensive agents

Cited by 7 publications

References 1 publication

Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry

High-resolution X-ray diffraction study of the complex between endothiapepsin and an oligopeptide inhibitor: the analysis of the inhibitor binding and description of the rigid body shift in the enzyme.

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