The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the deadly coronavirus disease 2019 (Covid-19) and is a concerning hazard to public health. This virus infects cells by establishing a contact between its spike protein (S-protein) and host human angiotensin-converting enzyme 2 (hACE2) receptor, subsequently initiating viral fusion. The inhibition of the interaction between the S-protein and hACE2 has immediately drawn attention amongst the scientific community, and the S-protein was considered the prime target to design vaccines and to develop affinity ligands for diagnostics and therapy. Several S-protein binders have been reported at a fast pace, ranging from antibodies isolated from immunised patients to de novo designed ligands, with some binders already yielding promising in vivo results in protecting against SARS-CoV-2. Natural, engineered and designed affinity ligands targeting the S-protein are herein summarised, focusing on molecular recognition aspects, whilst identifying preferred hot spots for ligand binding. This review serves as inspiration for the improvement of already existing ligands or for the design of new affinity ligands towards SARS-CoV-2 proteins. Lessons learnt from the Covid-19 pandemic are also important to consolidate tools and processes in protein engineering to enable the fast discovery, production and delivery of diagnostic, prophylactic, and therapeutic solutions in future pandemics.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 是造成 2019 年致命冠状病毒病 (Covid-19) 的罪魁祸首，对公众健康构成令人担忧的危害。该病毒通过在其刺突蛋白（S 蛋白）和宿主人血管紧张素转换酶 2 (hACE2) 受体之间建立接触，随后启动病毒融合来感染细胞。抑制 S 蛋白和 hACE2 之间的相互作用立即引起了科学界的关注，S 蛋白被认为是设计疫苗和开发用于诊断和治疗的亲和配体的主要目标。已经快速报道了几种 S 蛋白结合剂，范围从从免疫患者中分离的抗体到从头开始设计的配体，其中一些结合剂已经在体内产生了有希望的抗 SARS-CoV-2 保护结果。本文总结了靶向 S 蛋白的天然、工程和设计的亲和配体，重点关注分子识别方面，同时确定了配体结合的首选热点。这篇综述为改进现有配体或设计新的针对 SARS-CoV-2 蛋白的亲和配体提供了灵感。从 Covid-19 大流行中吸取的教训对于巩固蛋白质工程中的工具和过程也很重要，以便能够在未来的大流行中快速发现、生产和提供诊断、预防和治疗解决方案。