Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.
Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.
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药物设计策略，以避免直接作用的抗病毒药物和超越耐药性。
DOI：
10.1021/acs.chemrev.0c00648
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发表时间：
2021-03-24
期刊：
影响因子：
62.1
通讯作者：
Schiffer CA
中科院分区：
文献类型：
--
作者：
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
耐药性在许多疾病中普遍存在，导致治疗无效，造成严重的经济和健康后果。与其在事后接受耐药性，不如在药物设计和开发过程中纳入积极主动的策略，以最大限度地减少耐药性的影响。这些策略可以从我们在病毒疾病靶点方面的经验中得出，在这些靶点中，必须开发多代药物来对抗耐药性和避免抗病毒失败。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集中在了解直接作用抗病毒药物(DAA)耐药性的机制和结构基础上。综合方法在预测耐药性和效力方面表现出了希望。在这篇综述中，我们概述了这项针对HIV-1、丙型肝炎病毒和IAV的研究，以及从DAA耐药机制中吸取的教训。这些经验转化为合理的策略，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。虽然耐药性可能不是完全可以避免的，但合理的药物设计可以而且应该在药物开发之初纳入战略，以减少耐药性的流行。
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 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 HIV-1, HCV and IAV, 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.
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影响因子：
5.5
作者：
Cai, Yufeng;Schiffer, Celia A.
通讯作者：
Schiffer, Celia A.
影响因子：
5.5
作者：
Cai, Yufeng;Myint, Wazo;Paulsen, Janet L.;Schiffer, Celia A.;Ishima, Rieko;Yilmaz, Nese Kurt
通讯作者：
Yilmaz, Nese Kurt
影响因子：
0.2
作者：
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通讯作者：
Natt NK
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Ali, Akbar;Aydin, Cihan;Gildemeister, Reinhold;Romano, Keith P.;Cao, Hong;Oezen, Ayseguel;Soumana, Djade;Newton, Alicia;Petropoulos, Christos J.;Huang, Wei;Schiffer, Celia A.
通讯作者：
Schiffer, Celia A.
影响因子：
4.9
作者：
Callebaut, Christian;Stray, Kirsten;Cihlar, Tomas
通讯作者：
Cihlar, Tomas