Challenges for cysteamine stabilization, quantification, and biological effects improvement

Atallah, Carla; Charcosset, Catherine; Greige‐Gerges, Hélène

doi:10.1016/j.jpha.2020.03.007

Cited by 80 publications

(70 citation statements)

References 128 publications

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“…It is particularly appealing to re-purpose cysteamine and amifostine as COVID-19 treatments, because we show that micromolar concentrations of these dugs inhibit cell entry of SARS-CoV2. Cysteamine is used to treat cystinosis, a lysosomal storage disease characterized by cystine accumulation, and it is available in tablet (including extended release) and eye drop formulations 21 , 22 . Amifostine is used to treat complications of DNA-binding chemotherapeutic agents, and the trihydrate form is available as a lyophilized powder that is reconstituted for intravenous infusion 23 .…”

Section: Discussionmentioning

confidence: 99%

Thiol drugs decrease SARS-CoV-2 lung injuryin vivoand disrupt SARS-CoV-2 spike complex binding to ACE2in vitro

Khanna

Raymond

Charbit

et al. 2020

Preprint

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Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the SARS-CoV-2 spike protein is an envelope glycoprotein that binds angiotensin converting enzyme 2 as an entry receptor. The capacity of enveloped viruses to infect host cells depends on a precise thiol/disulfide balance in their surface glycoprotein complexes. To determine if cystines in the SARS-CoV-2 spike protein maintain a native binding interface that can be disrupted by drugs that cleave cystines, we tested if thiol-based drugs have efficacy in receptor binding and cell infection assays. We found that thiol-based drugs, cysteamine and WR-1065 (the active metabolite of amifostine) in particular, decrease binding of SARS-CoV-2 spike protein to its receptor, decrease the entry efficiency of SARS-CoV-2 spike pseudotyped virus, and inhibit SARS-CoV-2 live virus infection. Our findings uncover a vulnerability of SARS-CoV-2 to thiol-based drugs and provide rationale to test thiol-based drugs, especially cysteamine and amifostine, as novel treatments for COVID-19.One Sentence SummaryThiol-based drugs decrease binding of SARS-CoV-2 spike protein to its receptor and inhibit SARS-CoV-2 cell entry.

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Section: Discussionmentioning

confidence: 99%

Thiol drugs decrease SARS-CoV-2 lung injuryin vivoand disrupt SARS-CoV-2 spike complex binding to ACE2in vitro

Khanna

Raymond

Charbit

et al. 2020

Preprint

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“…Diverse analytical methods have been proposed in the literature to detect and quantify cysteamine in nonbiological and biological samples (plasma and urine) such as high-performance liquid chromatography (HPLC) with fluorescence and ultraviolet (UV) detection, high-voltage electrophoresis, ion-exchange column chromatography, enzymatic assay and gas chromatography with flame ionization and photometric detection. The choice of the most adequate method for each situation is difficult because it must be based on several parameters such as the type of sample [60]. Cysteamine structure does not present a chromophore in its structure, so that conventional analytical methods with UV absorbance or fluorescence detection are not useful if the molecule remains unchanged.…”

Section: Cysteamine Analytical Determination Methodsmentioning

confidence: 99%

“…The modified electrodes mentioned above are summarized in Table 5. Electrochemical methods showed a linear relationship between the catalytic oxidation peak and cysteamine concentration, being applicable in certain concentration ranges and different samples [60].…”

Section: Electrochemical Detectionmentioning

confidence: 98%

“…This degradation is due to a thiol functional group which immediately reacts with oxygen to produce a disulphide called cystamine, which is not effective at treating the cystine crystals located in the cornea [2,59]. This oxidation process takes place easily and rapidly in air and solution as a zero-order reaction, which indicates that the concentration of cysteamine decreases linearly with time [60]. The removal of oxygen from a solution of cysteamine by packing under nitrogen, and the addition of ascorbic acid, increase its stability.…”

Section: Cysteamine Structure and Stability Propertiesmentioning

confidence: 99%

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Recent Research in Ocular Cystinosis: Drug Delivery Systems, Cysteamine Detection Methods and Future Perspectives

et al. 2020

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Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs. Although renal damage prevails during initial stages, the deposition of cystine crystals in the cornea causes severe ocular manifestations. At present, cysteamine is the only topical effective treatment for ocular cystinosis. The lack of investment by the pharmaceutical industry, together with the limited stability of cysteamine, make it available only as two marketed presentations (Cystaran® and Cystadrops®) and as compounding formulations prepared in pharmacy departments. Even so, new drug delivery systems (DDSs) need to be developed, allowing more comfortable dosage schedules that favor patient adherence. In the last decades, different research groups have focused on the development of hydrogels, nanowafers and contact lenses, allowing a sustained cysteamine release. In parallel, different determination methods and strategies to increase the stability of the formulations have also been developed. This comprehensive review aims to compile all the challenges and advances related to new cysteamine DDSs, analytical determination methods, and possible future therapeutic alternatives for treating cystinosis.

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“…Indeed, cysteamine is thiol compound that is unstable in solution due to rapid oxidation of the sulfhydryl group 2 . A commercial sample of Clarite® Cysteamin (Dermage™, Sao Paulo‐Brazil) gel‐cream was analyzed at the Swiss Centre for Applied Human Toxicology (University of Geneva, Switzerland) through homogenization and extraction of cysteamine, to derivatization of a cysteamine compound coupled with N‐(1‐pyrenyl)maleimide (NPM).…”

mentioning

confidence: 99%

A comparative study of topical 5% cysteamine versus 4% hydroquinone in the treatment of facial melasma in women: the devil is in the detail

Lee

2020

Int J Dermatology

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Challenges for cysteamine stabilization, quantification, and biological effects improvement

Cited by 80 publications

References 128 publications

Thiol drugs decrease SARS-CoV-2 lung injuryin vivoand disrupt SARS-CoV-2 spike complex binding to ACE2in vitro

Thiol drugs decrease SARS-CoV-2 lung injuryin vivoand disrupt SARS-CoV-2 spike complex binding to ACE2in vitro

Recent Research in Ocular Cystinosis: Drug Delivery Systems, Cysteamine Detection Methods and Future Perspectives

A comparative study of topical 5% cysteamine versus 4% hydroquinone in the treatment of facial melasma in women: the devil is in the detail

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