Developing Drugs for the ‘Undruggable’

Sawyer, Abigail

doi:10.2144/btn-2020-0134

Cited by 10 publications

(4 citation statements)

References 9 publications

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“…The advantage of our approach is that peptides have good biodistribution, with cell entry facilitated by the conjugated TAT sequence; peptides are water-soluble and consist of naturally occurring amino acids [ 38 ]. Furthermore, the cellular interactome has been predicted to contain about 650,000 protein–protein interactions (PPIs) [ 39 , 40 , 41 , 42 ]. Peptides and peptidomimetics (modified peptide analogs that mimic the structural and functional characteristics of peptides in 3D space) can be harnessed to target PPIs, as about 15–40% of all PPIs are mediated by a short linear peptide [ 43 , 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury

et al. 2022

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Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI’s interaction with, and phosphorylation by, δPKC (ψTnI), and prevents tissue injury in a Langendorff model of myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced mitochondrial dysfunction. These data suggest that δPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/δPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury

et al. 2022

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“…The PROTAC strategy takes advantage of a natural degradation mechanism and rapidly degrades the POI, which effectively extends the scope of targets, including several undruggable ones ( Li, Song, et al, 2022 ), such as the transcription factors, nonenzymatic proteins, and scaffolding proteins ( Sawyer, 2020 ). As desirable candidates, several transcription factor-targeted PROTACs (e.g., ARV-110 ( 2 ), ARV-476, and CFT8634) are being used to conduct clinical trials ( Li, Song, et al, 2022 ).…”

Section: Advantages and Challenges To Antiviral Protacsmentioning

confidence: 99%

Antiviral PROTACs: Opportunity borne with challenge

Liang¹,

Wu²,

Lan³

et al. 2023

Cell Insight

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“…It uses the evaporative cooling method, which requires low energy to lower the ample space's temperature. According to the research done by scientists, the efficiency of cold-SNAP is four times higher than those of traditional air conditioning units, and the whole energy requirement is lower by about 75 percent without compromising its cooling ability [6]. Ac-cording to EHPA (European Heat Pump Association), the total sale of heat pumps is about 1.4 million units in Norway.…”

Section: Heat Pumpmentioning

confidence: 99%

Externalities Analysis on Heat Pump System (EU)

Li,

Cao,

et al. 2023

AEMPS

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This paper analysis the positive externalities of using heat pumps in European so-ciety to solve the high-temperature problem. Through the paper, heat pump as a potential solution to the climate problem, contemplating how it is done, why it is the best solution, and what are the positive externalities specifically to the City of London. The heat pump is renewable and can reduce carbon dioxide and sulfur emissions. In order to better introduce the benefits of heat pumps in those high-temperature cities, the author thus chooses to create a hypothetical city which is called M&M City. In the stimulating process, we predict the specific circum-stances of heat pumps that may be needed in the simulated city and associated packages, analyze the value and feasibility, as well as present the shortcomings and look to the future.

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Developing Drugs for the ‘Undruggable’

Abstract: There are up to 650,000 ‘undruggable’ protein-protein interactions (PPIs) in the human interactome that can be potentially considered as novel therapeutic targets. How does the ‘undruggable’ become ‘druggable’?

Cited by 10 publications

References 9 publications

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury

Antiviral PROTACs: Opportunity borne with challenge

Externalities Analysis on Heat Pump System (EU)

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