The Experts below are selected from a list of 14184 Experts worldwide ranked by ideXlab platform

Weiping Zheng - One of the best experts on this subject based on the ideXlab platform.

  • novel sirtuin inhibitory Warheads derived from the ne acetyl lysine analog l 2 amino 7 carboxamidoheptanoic acid
    Organic and Biomolecular Chemistry, 2015
    Co-Authors: Lingling Yan, Wenwen Zang, Weiping Zheng
    Abstract:

    Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead L-2-amino-7-carboxamidoheptanoic acid (L-ACAH, a close structural analog of Ne-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ∼2.4–6.6-fold stronger SIRT1/2/3 inhibitory warhead than L-ACAH. Carboxamide NH2-dodecylated and carboxymethylated analogs of L-ACAH were also identified as potent SIRT6 and SIRT5 inhibitory Warheads, respectively.

  • novel thiourea based sirtuin inhibitory Warheads
    Bioorganic & Medicinal Chemistry Letters, 2015
    Co-Authors: Wenwen Zang, Yujun Hao, Zhenghe Wang, Weiping Zheng
    Abstract:

    N(e)-Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism-based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared analogs of N(e)-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N(e)-methyl-thiocarbamoyl-lysine and N(e)-carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory Warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, N(e)-methyl-thiocarbamoyl-lysine was found in the study to be a ∼ 2.5-18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead N(e)-thiocarbamoyl-lysine.

Areg Danagoulian - One of the best experts on this subject based on the ideXlab platform.

  • experimental demonstration of an isotope sensitive warhead verification technique using nuclear resonance fluorescence
    Proceedings of the National Academy of Sciences of the United States of America, 2018
    Co-Authors: Jayson R Vavrek, Brian S Henderson, Areg Danagoulian
    Abstract:

    Future nuclear arms reduction efforts will require technologies to verify that Warheads slated for dismantlement are authentic without revealing any sensitive weapons design information to international inspectors. Despite several decades of research, no technology has met these requirements simultaneously. Recent work by Kemp et al. [Kemp RS, Danagoulian A, Macdonald RR, Vavrek JR (2016) Proc Natl Acad Sci USA 113:8618–8623] has produced a novel physical cryptographic verification protocol that approaches this treaty verification problem by exploiting the isotope-specific nature of nuclear resonance fluorescence (NRF) measurements to verify the authenticity of a warhead. To protect sensitive information, the NRF signal from the warhead is convolved with that of an encryption foil that contains key warhead isotopes in amounts unknown to the inspector. The convolved spectrum from a candidate warhead is statistically compared against that from an authenticated template warhead to determine whether the candidate itself is authentic. Here we report on recent proof-of-concept warhead verification experiments conducted at the Massachusetts Institute of Technology. Using high-purity germanium (HPGe) detectors, we measured NRF spectra from the interrogation of proxy “genuine” and “hoax” objects by a 2.52 MeV endpoint bremsstrahlung beam. The observed differences in NRF intensities near 2.2 MeV indicate that the physical cryptographic protocol can distinguish between proxy genuine and hoax objects with high confidence in realistic measurement times.

  • Nuclear disarmament verification via resonant phenomena
    Nature Publishing Group, 2018
    Co-Authors: Jake J. Hecla, Areg Danagoulian
    Abstract:

    Authenticating a nuclear warhead without revealing its design is a challenge. Here the authors discuss a nuclear disarmament verification method based on neutron resonance analysis which is sensitive to the isotopic composition of the materials used in Warheads

  • physical cryptographic verification of nuclear Warheads
    Proceedings of the National Academy of Sciences of the United States of America, 2016
    Co-Authors: Scott R Kemp, Areg Danagoulian, Ruaridh R Macdonald, Jayson Robert Vavrek
    Abstract:

    How does one prove a claim about a highly sensitive object such as a nuclear weapon without revealing information about the object? This paradox has challenged nuclear arms control for more than five decades. We present a mechanism in the form of an interactive proof system that can validate the structure and composition of an object, such as a nuclear warhead, to arbitrary precision without revealing either its structure or composition. We introduce a tomographic method that simultaneously resolves both the geometric and isotopic makeup of an object. We also introduce a method of protecting information using a provably secure cryptographic hash that does not rely on electronics or software. These techniques, when combined with a suitable protocol, constitute an interactive proof system that could reject hoax items and clear authentic Warheads with excellent sensitivity in reasonably short measurement times.

Helene Barreteau - One of the best experts on this subject based on the ideXlab platform.

  • a road map for prioritizing Warheads for cysteine targeting covalent inhibitors
    European Journal of Medicinal Chemistry, 2018
    Co-Authors: Peter Abranyibalogh, Laszlo Petri, Timea Imre, Peter A Szijj, Andrea Scarpino, Martina Hrast, Ana Mitrovic, Ursa Pecar Fonovic, Krisztina Nemeth, Helene Barreteau
    Abstract:

    Abstract Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied Warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently. In contrast, we suggest that the reactive warhead itself should be tailored to the reactivity of the specific cysteine being targeted, and we describe a strategy to achieve this goal. Here, we have extended and systematically explored the available organic chemistry toolbox and characterized a large number of Warheads representing different chemistries. We demonstrate that in addition to the common Michael addition, there are other nucleophilic addition, addition-elimination, nucleophilic substitution and oxidation reactions suitable for specific covalent protein modification. Importantly, we reveal that Warheads for these chemistries impact the reactivity and specificity of covalent fragments at both protein and proteome levels. By integrating surrogate reactivity and selectivity models and subsequent protein assays, we define a road map to help enable new or largely unexplored covalent chemistries for the optimization of cysteine targeting inhibitors.

  • A road map for prioritizing Warheads for cysteine targeting covalent inhibitors
    European Journal of Medicinal Chemistry, 2018
    Co-Authors: Peter Abranyi-balogh, Laszlo Petri, Timea Imre, Peter A Szijj, Andrea Scarpino, Martina Hrast, Ana Mitrovic, Ursa Pecar Fonovic, Krisztina Nemeth, Helene Barreteau
    Abstract:

    Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied Warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently. In contrast, we suggest that the reactive warhead itself should be tailored to the reactivity of the specific cysteine being targeted, and we describe a strategy to achieve this goal. Here, we have extended and systematically explored the available organic chemistry toolbox and characterized a large number of Warheads representing different chemistries. We demonstrate that in addition to the common Michael addition, there are other nucleophilic addition, addition-elimination, nucleophilic substitution and oxidation reactions suitable for specific covalent protein modification. Importantly, we reveal that Warheads for these chemistries impact the reactivity and specificity of covalent fragments at both protein and proteome levels. By integrating surrogate reactivity and selectivity models and subsequent protein assays, we define a road map to help enable new or largely unexplored covalent chemistries for the optimization of cysteine targeting inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.

Wenwen Zang - One of the best experts on this subject based on the ideXlab platform.

  • novel sirtuin inhibitory Warheads derived from the ne acetyl lysine analog l 2 amino 7 carboxamidoheptanoic acid
    Organic and Biomolecular Chemistry, 2015
    Co-Authors: Lingling Yan, Wenwen Zang, Weiping Zheng
    Abstract:

    Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead L-2-amino-7-carboxamidoheptanoic acid (L-ACAH, a close structural analog of Ne-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ∼2.4–6.6-fold stronger SIRT1/2/3 inhibitory warhead than L-ACAH. Carboxamide NH2-dodecylated and carboxymethylated analogs of L-ACAH were also identified as potent SIRT6 and SIRT5 inhibitory Warheads, respectively.

  • novel thiourea based sirtuin inhibitory Warheads
    Bioorganic & Medicinal Chemistry Letters, 2015
    Co-Authors: Wenwen Zang, Yujun Hao, Zhenghe Wang, Weiping Zheng
    Abstract:

    N(e)-Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism-based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared analogs of N(e)-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N(e)-methyl-thiocarbamoyl-lysine and N(e)-carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory Warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, N(e)-methyl-thiocarbamoyl-lysine was found in the study to be a ∼ 2.5-18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead N(e)-thiocarbamoyl-lysine.

Danagoulian Areg - One of the best experts on this subject based on the ideXlab platform.

  • A physically cryptographic warhead verification system using neutron induced nuclear resonances
    'Springer Science and Business Media LLC', 2020
    Co-Authors: Engel, Ezra M., Danagoulian Areg
    Abstract:

    Arms control treaties are necessary to reduce the large stockpiles of the nuclear weapons that constitute one of the biggest dangers to the world. However, an impactful treaty hinges on effective inspection exercises to verify the participants’ compliance to the treaty terms. Such procedures would require verification of the authenticity of a warhead undergoing dismantlement. Previously proposed solutions lacked the combination of isotopic sensitivity and information security. Here we present the experimental feasibility proof of a technique that uses neutron induced nuclear resonances and is sensitive to the combination of isotopics and geometry. The information is physically encrypted to prevent the leakage of sensitive information. Our approach can significantly increase the trustworthiness of future arms control treaties while expanding their scope to include the verified dismantlement of nuclear Warheads themselves.United States. National Nuclear Security Administration (Award DE-NA0002534

  • A physically cryptographic warhead verification system using neutron induced nuclear resonances
    'Springer Science and Business Media LLC', 2019
    Co-Authors: Engel, Ezra M., Danagoulian Areg
    Abstract:

    Arms control treaties are necessary to reduce the large stockpiles of the nuclear weapons that constitute one of the biggest dangers to the world. However, an impactful treaty hinges on effective inspection exercises to verify the participants' compliance to the treaty terms. Such procedures would require verification of the authenticity of a warhead undergoing dismantlement. Previously proposed solutions lacked the combination of isotopic sensitivity and information security. Here we present the experimental feasibility proof of a novel technique that uses neutron induced nuclear resonances and is sensitive to the combination of isotopics and geometry. The information is physically encrypted to prevent the leakage of sensitive information. Our approach can significantly increase the trustworthiness of future arms control treaties while expanding their scope to include the verified dismantlement of nuclear Warheads themselves

  • Experimental demonstration of an isotope-sensitive warhead verification technique using nuclear resonance fluorescence
    'Proceedings of the National Academy of Sciences', 2018
    Co-Authors: Vavrek, Jayson R, Henderson, Brian S, Danagoulian Areg
    Abstract:

    Future nuclear arms reduction efforts will require technologies to verify that Warheads slated for dismantlement are authentic without revealing any sensitive weapons design information to international inspectors. Despite several decades of research, no technology has met these requirements simultaneously. Recent work by Kemp et al. [Kemp RS, Danagoulian A, Macdonald RR, Vavrek JR (2016) Proc Natl Acad Sci USA 113:8618--8623] has produced a novel physical cryptographic verification protocol that approaches this treaty verification problem by exploiting the isotope-specific nature of nuclear resonance fluorescence (NRF) measurements to verify the authenticity of a warhead. To protect sensitive information, the NRF signal from the warhead is convolved with that of an encryption foil that contains key warhead isotopes in amounts unknown to the inspector. The convolved spectrum from a candidate warhead is statistically compared against that from an authenticated template warhead to determine whether the candidate itself is authentic. Here we report on recent proof-of-concept warhead verification experiments conducted at the Massachusetts Institute of Technology. Using high-purity germanium (HPGe) detectors, we measured NRF spectra from the interrogation of proxy 'genuine' and 'hoax' objects by a 2.52 MeV endpoint bremsstrahlung beam. The observed differences in NRF intensities near 2.2 MeV indicate that the physical cryptographic protocol can distinguish between proxy genuine and hoax objects with high confidence in realistic measurement times.Comment: 38 pages, 19 figures; revised for peer review and copy editing; addition to SI for realistic scenario projections; minor length reduction for journal requirement

  • Nuclear disarmament verification via resonant phenomena
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Hecla, Jake J., Danagoulian Areg
    Abstract:

    Nuclear disarmament treaties are not sufficient in and of themselves to neutralize the existential threat of the nuclear weapons. Technologies are necessary for verifying the authenticity of the nuclear Warheads undergoing dismantlement before counting them toward a treaty partner's obligation. Here we present a concept that leverages isotope-specific nuclear resonance phenomena to authenticate a warhead's fissile components by comparing them to a previously authenticated template. All information is encrypted in the physical domain in a manner that amounts to a physical zero-knowledge proof system. Using Monte Carlo simulations, the system is shown to reveal no isotopic or geometric information about the weapon, while readily detecting hoaxing attempts. This nuclear technique can dramatically increase the reach and trustworthiness of future nuclear disarmament treaties.United States. Department of Energy (Award DE-NA0002534