The limited treatment options for the increasing occurrence of Lassa hemorrhagic fever in West Africa poses an urgent need for the discovery and development of novel therapeutics. Dietary supplements, especially natural products that are edible and safe for human use, are a good source of drug discovery with potential for uncovering novel applications. In this study, we tested 40 natural products of dietary supplements and identified capsaicin, a common dietary supplement abundant in chili peppers, as an inhibitor of Lassa virus (LASV) entry with EC₅₀ of 6.9–10.0 μmol/L using an HIV based pseudovirus platform. Capsaicin inhibits the entry of five LASV strains but not against the Old World arenavirus lymphocytic choriomeningitis virus (LCMV), showing a preferential activity against LASV. Capsaicin inhibits LASV entry by blocking the pH dependent viral fusion through affecting the stable signal peptide (SSP)-GP2 transmembrane (GP2_TM) region of the LASV surface glycoprotein. Mutational study revealed the key residues Ala25, Val431, Phe434 and Val435 in SSP-GP2_TM region in capsaicin's antiviral effect. This study for the first time reveals a direct acting antiviral effect of capsaicin against the hemorrhagic fever causing LASV, providing detailed interaction hot spots in the unique SSP-GP2_TM interface of LASV glycoprotein that is crucial in fusion inhibition, and offering a new strategy in discovering and developing antivirals from natural products that are safe for human use.

西非拉沙出血热发病率不断上升，治疗选择有限，迫切需要发现和开发新的治疗方法。膳食补充剂，特别是可食用且可供人类安全使用的天然产品，是药物发现的良好来源，具有发现新应用的潜力。在这项研究中，我们测试了 40 种天然膳食补充剂产品，并使用基于 HIV 的假病毒鉴定了辣椒素（一种富含辣椒的常见膳食补充剂）作为拉沙病毒 (LASV) 进入的抑制剂，其 EC ₅₀为 6.9–10.0 μmol/L平台。辣椒素可抑制五种 LASV 病毒株的进入，但不能抑制旧世界沙粒病毒淋巴细胞性脉络膜脑膜炎病毒 (LCMV)，显示出对 LASV 的优先活性。辣椒素通过影响 LASV 表面糖蛋白的稳定信号肽 (SSP)-GP2 跨膜 (GP2 _TM ) 区域来阻断 pH 依赖性病毒融合，从而抑制 LASV 进入。突变研究揭示了辣椒素抗病毒作用中SSP-GP2 _TM区域的关键残基Ala25、Val431、Phe434和Val435。这项研究首次揭示了辣椒素对引起 LASV 的出血热的直接抗病毒作用，提供了 LASV 糖蛋白独特的 SSP-GP2 _TM界面中对融合抑制至关重要的详细相互作用热点，并提供了一种新策略从人类安全使用的天然产品中发现和开发抗病毒药物。