Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
School of Biomedical Sciences & Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
Pharmacol Res Perspect. 2022 Feb;10(1):e00922. doi: 10.1002/prp2.922.
Why a systems analysis view of this pandemic? The current pandemic has inflicted almost unimaginable grief, sorrow, loss, and terror at a global scale. One of the great ironies with the COVID-19 pandemic, particularly early on, is counter intuitive. The speed at which specialized basic and clinical sciences described the details of the damage to humans in COVID-19 disease has been impressive. Equally, the development of vaccines in an amazingly short time interval has been extraordinary. However, what has been less well understood has been the fundamental elements that underpin the progression of COVID-19 in an individual and in populations. We have used systems analysis approaches with human physiology and pharmacology to explore the fundamental underpinnings of COVID-19 disease. Pharmacology powerfully captures the thermodynamic characteristics of molecular binding with an exogenous entity such as a virus and its consequences on the living processes well described by human physiology. Thus, we have documented the passage of SARS-CoV-2 from infection of a single cell to species jump, to tropism, variant emergence and widespread population infection. During the course of this review, the recurrent observation was the efficiency and simplicity of one critical function of this virus. The lethality of SARS-CoV-2 is due primarily to its ability to possess and use a variable surface for binding to a specific human target with high affinity. This binding liberates Gibbs free energy (GFE) such that it satisfies the criteria for thermodynamic spontaneity. Its binding is the prelude to human host cellular entry and replication by the appropriation of host cell constituent molecules that have been produced with a prior energy investment by the host cell. It is also a binding that permits viral tropism to lead to high levels of distribution across populations with newly formed virions. This thermodynamic spontaneity is repeated endlessly as infection of a single host cell spreads to bystander cells, to tissues, to humans in close proximity and then to global populations. The principal antagonism of this process comes from SARS-CoV-2 itself, with its relentless changing of its viral surface configuration, associated with the inevitable emergence of variants better configured to resist immune sequestration and importantly with a greater affinity for the host target and higher infectivity. The great value of this physiological and pharmacological perspective is that it reveals the fundamental thermodynamic underpinnings of SARS-CoV-2 infection.
为什么要从系统分析的角度来看待这场大流行呢？当前的大流行在全球范围内造成了难以想象的悲痛、悲伤、损失和恐惧。COVID-19 大流行的一个巨大讽刺之处在于，它违背了直觉。从基础科学和临床医学的角度描述 COVID-19 疾病对人类造成的损害细节的速度令人印象深刻。同样，在如此短的时间内开发出疫苗也是非凡的。然而，人们对支撑 COVID-19 在个体和人群中进展的基本要素理解得还不够。我们使用系统分析方法研究了人类生理学和药理学，以探索 COVID-19 疾病的基本原理。药理学有力地捕捉了分子与外源性实体（如病毒）结合的热力学特征及其对人类生理学很好描述的生命过程的影响。因此，我们记录了 SARS-CoV-2 从单个细胞感染到物种跳跃、嗜性、变体出现和广泛人群感染的过程。在这篇综述的过程中，我们反复观察到这种病毒的一个关键功能的效率和简单性。SARS-CoV-2 的致命性主要是由于它能够拥有和使用可变表面，以高亲和力与特定的人类靶标结合。这种结合释放出吉布斯自由能（GFE），使其满足热力学自发性的标准。它的结合是人类宿主细胞进入和复制的前奏，通过利用宿主细胞已经产生的组成分子，这些分子是宿主细胞以前投入能量产生的。它也是一种允许病毒嗜性导致新形成的病毒颗粒在人群中广泛分布的结合。随着单个宿主细胞的感染传播到旁观者细胞、组织、近距离的人类，然后传播到全球人群，这种热力学自发性会不断重复。这个过程的主要拮抗作用来自 SARS-CoV-2 本身，它不断改变其病毒表面结构，伴随着不可避免的变体出现，这些变体更好地配置来抵抗免疫隔离，更重要的是，与宿主靶标具有更高的亲和力和更高的感染力。这种生理学和药理学观点的巨大价值在于，它揭示了 SARS-CoV-2 感染的基本热力学基础。
