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Constraining evolution and avoiding drug resistance.

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We combine a variety of experimental and computational techniques to understand the molecular basis of drug resistance and pay attention to the ways that the natural substrate specificity is maintained by the resistant viral variants. Our new paradigm of drug design minimizes chances of resistance.

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We've realized that through understanding the molecular mechanism by which the disease process occurs we could develop inhibitors that block the disease in such a way that the likelihood of resistance occurring is greatly reduced. 

How We Do It_Schiffer.png

We combine a variety of experimental and computational techniques to understand the molecular basis of drug resistance. 

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We are a collaborative team of scientists dedicated to understanding and thwarting drug resistance.


Research Highlights

Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state

Maiti A, Hedger AK, Myint W, Balachandran V, Watts JK, Schiffer CA, Matsuo H. Nat Commun. 2022 

 oi: 10.1038/s41467-022-34752-1. PMID: 36402773; PMCID: PMC9675756.

 

Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance

Shaqra AM, Zvornicanin SN, Huang QYJ, Lockbaum GJ, Knapp M, Tandeske L, Bakan DT, Flynn J, Bolon DNA, Moquin S, Dovala D, Kurt Yilmaz N, Schiffer CA. Nat Commun. 2022 

doi: 10.1038/s41467-022-31210-w. PMID: 35729165; PMCID: PMC9211792.

Quantitative structural analysis of influenza virus by cryo-electron tomography and convolutional neural networks

Qiuyu J. Huang, Kangkang Song, Chen Xu, Daniel N.A. Bolon, Jennifer P. Wang, Robert W. Finberg, Celia A. Schiffer, Mohan Somasundaran. Structure March 2022.
DOI:  10.1016/j.str.2022.02.014

 

Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond

Matthew AN, Leidner F, Lockbaum GJ, Henes M, Zephyr J, Hou S, Rao DN, Timm J, Rusere LN, Ragland DA, Paulsen JL, Prachanronarong K, Soumana DI, Nalivaika EA, Kurt Yilmaz N, Ali A, Schiffer CA. Chem Rev. 2021  doi: 10.1021/acs.chemrev.0c00648. Epub 2021 Jan 7. PMID: 33410674; PMCID: PMC8126998.
 
 



 

Latest Schiffer Lab news as reported by the UMass Chan Communications Office

Recent Publications

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  • Structural Analysis of Inhibitor Binding to Enterovirus-D68 3C Protease

    Saturday, January 25, 2025
    Author(s): Vincent N Azzolino,Ala M Shaqra,Akbar Ali,Nese Kurt Yilmaz,Celia A Schiffer
    Source: Viruses
    Enterovirus-D68 (EV68) continues to present as a global health issue causing respiratory illness and outbreaks associated with long-lasting neurological disease, with no antivirals or specific treatme...

  • Direct delivery of Cas-embedded cytosine base editors as ribonucleoprotein complexes for efficient and accurate editing of clinically relevant targets

    Monday, December 16, 2024
    Author(s): Jeong Min Lee,Jing Zeng,Pengpeng Liu,My Anh Nguyen,Diego Suchenski Loustaunau,Daniel E Bauer,Nese Kurt Yilmaz,Scot A Wolfe,Celia A Schiffer
    Source: Nucleic acids research
    Recently, cytosine base editors (CBEs) have emerged as a promising therapeutic tool for specific editing of single nucleotide variants and disrupting specific genes associated with disease. Despite th...

  • Efficient convergent synthesis of 1,3-diazepinone nucleosides by ring-closing metathesis and direct glycosylation

    Thursday, November 21, 2024
    Author(s): Adam K Hedger,Jonathan Findell,Dinesh S Barak,Celia A Schiffer,Jonathan K Watts,Akbar Ali
    Source: RSC advances
    A new and highly efficient ring-closing metathesis-based strategy was developed for the synthesis of the cyclic urea 1,3-diazepinone, presenting significant improvement upon previous methods. Using a ...

  • Virion-associated influenza hemagglutinin clusters upon sialic acid binding visualized by cryo-electron tomography

    Monday, October 28, 2024
    Author(s): Qiuyu J Huang,Ryan Kim,Kangkang Song,Nikolaus Grigorieff,James B Munro,Celia A Schiffer,Mohan Somasundaran
    Source: bioRxiv : the preprint server for biology
    Influenza viruses are enveloped, negative sense single-stranded RNA viruses covered in a dense layer of glycoproteins. Hemagglutinin (HA) accounts for 80-90% of influenza glycoprotein and plays a role...

  • Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance

    Saturday, September 28, 2024
    Author(s): Vincent N Azzolino,Ala M Shaqra,Akbar Ali,Nese Kurt Yilmaz,Celia A Schiffer
    Source: Viruses
    Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there ar...

  • FcRn-enhancing mutations lead to increased and prolonged levels of the HIV CCR5-blocking monoclonal antibody leronlimab in the fetuses and newborns of pregnant rhesus macaques

    Thursday, September 26, 2024
    Author(s): Joanna Zikos,Gabriela M Webb,Helen L Wu,Jason S Reed,Jennifer Watanabe,Jodie L Usachenko,Ala M Shaqra,Celia A Schiffer,Koen K A Van Rompay,Jonah B Sacha,Diogo M Magnani
    Source: mAbs
    Prenatal administration of monoclonal antibodies (mAbs) is a strategy that could be exploited to prevent viral infections during pregnancy and early life. To reach protective levels in fetuses, mAbs m...

  • Increasing intracellular dNTP levels improves prime editing efficiency

    Wednesday, September 25, 2024
    Author(s): Pengpeng Liu,Karthikeyan Ponnienselvan,Thomas Nyalile,Sarah Oikemus,Anya T Joynt,Sukanya Iyer,Karen Kelly,Dongsheng Guo,Pyae P Kyawe,Emma Vanderleeden,Sambra D Redick,Lei Huang,Zexiang Chen,Jeong Min ...
    Source: Nature biotechnology
    In primary cell types, intracellular deoxynucleotide triphosphate (dNTP) levels are tightly regulated in a cell cycle-dependent manner. We report that prime editing efficiency is increased by mutation...

  • Next generation APOBEC3 inhibitors: Optimally designed for potency and nuclease stability

    Monday, September 16, 2024
    Author(s): Adam K Hedger,Wazo Myint,Jeong Min Lee,Diego Suchenski-Loustaunau,Vanivilasini Balachandran,Ala M Shaqra,Nese Kurt-Yilmaz,Jonathan K Watts,Hiroshi Matsuo,Celia A Schiffer
    Source: bioRxiv : the preprint server for biology
    APOBEC3 (or A3) enzymes have emerged as potential therapeutic targets due to their role in introducing heterogeneity in viruses and cancer, often leading to drug resistance. Inhibiting these enzymes h...

  • Enabling equitable and affordable access to novel therapeutics for pandemic preparedness and response via creative intellectual property agreements

    Monday, August 26, 2024
    Author(s): Ed J Griffen,Pascale Boulet,ASAP Discovery Center,COVID Moonshot
    Source: Wellcome open research
    The COVID-19 pandemic demonstrated that the current purely market-driven approaches to drug discovery and development alone are insufficient to drive equitable access to new therapies either in prepar...

  • Contributions of Hyperactive Mutations in Mpro from SARS-CoV-2 to Drug Resistance

    Tuesday, March 12, 2024
    Author(s): Julia M Flynn,Sarah N Zvornicanin,Tenzin Tsepal,Ala M Shaqra,Nese Kurt Yilmaz,Weiping Jia,Stephanie Moquin,Dustin Dovala,Celia A Schiffer,Daniel N A Bolon
    Source: ACS infectious diseases
    The appearance and spread of mutations that cause drug resistance in rapidly evolving diseases, including infections by the SARS-CoV-2 virus, are major concerns for human health. Many drugs target enz...
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Molecular illustrations on this webpage were generated by Leonora Martínez-Núñez, PhD.