Reversible lysine-targeted probes reveal residence time-based kinase selectivity

Yang, Tangpo; Cuesta, Adolfo; Wan, Xiaobo; Craven, Gregory B.; Hirakawa, Brad; Khamphavong, Penney; May, Jeffrey R.; Kath, John C.; Lapek, John D.; Niessen, Sherry; Burlingame, Alma L.; Carelli, Jordan D; Taunton, Jack

doi:10.1038/s41589-022-01019-1

“…To circumvent this issue, we synthesized an analogue of S4_APBA-3 , which installs a salicylaldehyde (SA) as a surrogate warhead of APBA (Figure S8). SA is known to covalently bind lysines to give an imine adduct that is amenable to NaBH 4 reduction . The peptide S4_SA yielded similar SrtA binding affinity with S4_APBA-3 (Figure S8).…”

Section: Resultsmentioning

confidence: 93%

“…SA is known to covalently bind lysines to give an imine adduct that is amenable to NaBH 4 reduction. 33 The peptide S4_SA yielded similar SrtA binding affinity with S4_APBA-3 (Figure S8). When subjected to NaBH 4 reduction, the mixture of S4_SA and SrtA yielded a 1:1 covalent adduct as revealed by mass spectrometry (Figure S9).…”

Section: ■ Introductionmentioning

confidence: 86%

Lysine-Targeted Reversible Covalent Ligand Discovery for Proteins via Phage Display

Zheng

¹

,

Chen

²

,

Li

³

et al. 2022

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Binding via reversible covalent bond formation presents a novel and powerful mechanism to enhance the potency of synthetic inhibitors for therapeutically important proteins. Work on this front has yielded the anticancer drug bortezomib as well as the antisickling drug voxelotor. However, the rational design of reversible covalent inhibitors remains difficult even when noncovalent inhibitors are available as a scaffold. Herein, we report chemically modified phage libraries, both linear and cyclic, that incorporate 2-acetylphenylboronic acid (APBA) as a warhead to bind lysines via reversible iminoboronate formation. To demonstrate their utility, these APBA-presenting phage libraries were screened against sortase A of Staphylococcus aureus, as well as the spike protein of SARS-CoV-2. For both protein targets, peptide ligands were readily identified with single-digit micromolar potency and excellent specificity, enabling live-cell sortase inhibition and highly sensitive spike protein detection, respectively. Furthermore, our structure–activity studies unambiguously demonstrate the benefit of the APBA warhead for protein binding. Overall, this contribution shows for the first time that reversible covalent inhibitors can be developed via phage display for a protein of interest. The phage display platform should be widely applicable to proteins including those involved in protein–protein interactions.

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“…Lack of significant toxicity of Voxelotor was supported by the recent $5.4 billion acquisition of Global Blood Therapeutics by Pfizer. Interestingly, it was published this year that the time spent by Voxelotor correctly bound to hemoglobin (the residence time) was "dramatically enhanced" by a hydroxyl group ortho to the aldehyde moiety of Voxelotor, thereby facilitating a favorable equilibration of the drug correctly bound to hemoglobin 32 . The lack of toxicity reported for Tucaresol in animal and human studies cited above is in agreement with this lack of toxicity observed with Voxelotor.…”

Section: Tucaresol Preclinical Studiesmentioning

confidence: 99%

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

Penney¹,

Zacharie²,

Duceppe³

2022

Preprint

0

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The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

show abstract

“…Interestingly, it was published this year that the time spent by Voxelotor correctly bound to hemoglobin (the residence time) was "dramatically enhanced" by a hydroxyl group ortho to the aldehyde moiety of Voxelotor, thereby facilitating a favorable equilibration of the drug correctly bound to hemoglobin 32 . The lack of toxicity reported for Tucaresol in animal and human studies cited above is in agreement with this lack of toxicity observed with Voxelotor.…”

Section: Tucaresol Preclinical Studiesmentioning

confidence: 99%

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

Penney¹,

Zacharie²,

Duceppe³

2022

Preprint

0

View full text Add to dashboard Cite

The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

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Reversible lysine-targeted probes reveal residence time-based kinase selectivity

Cited by 63 publications

References 51 publications

Lysine-Targeted Reversible Covalent Ligand Discovery for Proteins via Phage Display

Lysine-Targeted Reversible Covalent Ligand Discovery for Proteins via Phage Display

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

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