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Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond
Chemical Reviews ( IF 51.4 ) Pub Date : 2021-01-07 , DOI: 10.1021/acs.chemrev.0c00648 Ashley N Matthew 1 , Florian Leidner 1 , Gordon J Lockbaum 1 , Mina Henes 1 , Jacqueto Zephyr 1 , Shurong Hou 1 , Desaboini Nageswara Rao 1 , Jennifer Timm 1 , Linah N Rusere 1 , Debra A Ragland 1 , Janet L Paulsen 1 , Kristina Prachanronarong 1 , Djade I Soumana 1 , Ellen A Nalivaika 1 , Nese Kurt Yilmaz 1 , Akbar Ali 1 , Celia A Schiffer 1
Chemical Reviews ( IF 51.4 ) Pub Date : 2021-01-07 , DOI: 10.1021/acs.chemrev.0c00648 Ashley N Matthew 1 , Florian Leidner 1 , Gordon J Lockbaum 1 , Mina Henes 1 , Jacqueto Zephyr 1 , Shurong Hou 1 , Desaboini Nageswara Rao 1 , Jennifer Timm 1 , Linah N Rusere 1 , Debra A Ragland 1 , Janet L Paulsen 1 , Kristina Prachanronarong 1 , Djade I Soumana 1 , Ellen A Nalivaika 1 , Nese Kurt Yilmaz 1 , Akbar Ali 1 , Celia A Schiffer 1
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Drug resistance is prevalent across many diseases, rendering therapies ineffective with severe financial and health consequences. Rather than accepting resistance after the fact, proactive strategies need to be incorporated into the drug design and development process to minimize the impact of drug resistance. These strategies can be derived from our experience with viral disease targets where multiple generations of drugs had to be developed to combat resistance and avoid antiviral failure. Significant efforts including experimental and computational structural biology, medicinal chemistry, and machine learning have focused on understanding the mechanisms and structural basis of resistance against direct-acting antiviral (DAA) drugs. Integrated methods show promise for being predictive of resistance and potency. In this review, we give an overview of this research for human immunodeficiency virus type 1, hepatitis C virus, and influenza virus and the lessons learned from resistance mechanisms of DAAs. These lessons translate into rational strategies to avoid resistance in drug design, which can be generalized and applied beyond viral targets. While resistance may not be completely avoidable, rational drug design can and should incorporate strategies at the outset of drug development to decrease the prevalence of drug resistance.
中文翻译：
避免直接作用抗病毒药物及其他药物耐药性的药物设计策略
耐药性在许多疾病中普遍存在，导致治疗无效并造成严重的经济和健康后果。需要将积极主动的策略纳入药物设计和开发过程中，以尽量减少耐药性的影响，而不是事后接受耐药性。这些策略可以源自我们在病毒性疾病靶标方面的经验，其中必须开发多代药物来对抗耐药性并避免抗病毒失败。包括实验和计算结构生物学、药物化学和机器学习在内的重大努力都集中在了解直接作用抗病毒（DAA）药物耐药性的机制和结构基础。综合方法有望预测耐药性和效力。在这篇综述中，我们概述了人类免疫缺陷病毒 1 型、丙型肝炎病毒和流感病毒的研究以及从 DAA 耐药机制中吸取的教训。这些经验教训转化为合理的策略，以避免药物设计中的耐药性，这些策略可以推广并应用于病毒靶标之外。虽然耐药性可能无法完全避免，但合理的药物设计可以而且应该在药物开发之初就纳入策略，以降低耐药性的发生率。
更新日期：2021-01-07
中文翻译：
避免直接作用抗病毒药物及其他药物耐药性的药物设计策略
耐药性在许多疾病中普遍存在，导致治疗无效并造成严重的经济和健康后果。需要将积极主动的策略纳入药物设计和开发过程中，以尽量减少耐药性的影响，而不是事后接受耐药性。这些策略可以源自我们在病毒性疾病靶标方面的经验，其中必须开发多代药物来对抗耐药性并避免抗病毒失败。包括实验和计算结构生物学、药物化学和机器学习在内的重大努力都集中在了解直接作用抗病毒（DAA）药物耐药性的机制和结构基础。综合方法有望预测耐药性和效力。在这篇综述中，我们概述了人类免疫缺陷病毒 1 型、丙型肝炎病毒和流感病毒的研究以及从 DAA 耐药机制中吸取的教训。这些经验教训转化为合理的策略，以避免药物设计中的耐药性，这些策略可以推广并应用于病毒靶标之外。虽然耐药性可能无法完全避免，但合理的药物设计可以而且应该在药物开发之初就纳入策略，以降低耐药性的发生率。
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