School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Department of Biomedical and Clinical Sciences (BKV), Division of Molecular Medicine and Virology, Mucosa infection och inflammation Center (MIIC), Linköping University, Linköping, Sweden.
PLoS One. 2022 Nov 30;17(11):e0278419. doi: 10.1371/journal.pone.0278419. eCollection 2022.
Potent broad-spectrum antiviral agents are urgently needed to combat existing and emerging viral infections. This is particularly important considering that vaccine development is a costly and time consuming process and that viruses constantly mutate and render the vaccine ineffective. Antimicrobial peptides (AMP), such as bacteriocins, are attractive candidates as antiviral agents against enveloped viruses. One of these bacteriocins is PLNC8 αβ, which consists of amphipathic peptides with positive net charges that display high affinity for negatively charged pathogen membrane structures, including phosphatidylserine rich lipid membranes of viral envelopes. Due to the morphological and physiological differences between viral envelopes and host cell plasma membranes, PLNC8 αβ is thought to have high safety profile by specifically targeting viral envelopes without effecting host cell membranes. In this study, we have tested the antiviral effects of PLNC8 αβ against the flaviviruses Langat and Kunjin, coronavirus SARS-CoV-2, influenza A virus (IAV), and human immunodeficiency virus-1 (HIV-1). The concentration of PLNC8 αβ that is required to eliminate all the infective virus particles is in the range of nanomolar (nM) to micromolar (μM), which is surprisingly efficient considering the high content of cholesterol (8-35%) in their lipid envelopes. We found that viruses replicating in the endoplasmic reticulum (ER)/Golgi complex, e.g. SARS-CoV-2 and flaviviruses, are considerably more susceptible to PLNC8 αβ, compared to viruses that acquire their lipid envelope from the plasma membrane, such as IAV and HIV-1. Development of novel broad-spectrum antiviral agents can significantly benefit human health by rapidly and efficiently eliminating infectious virions and thereby limit virus dissemination and spreading between individuals. PLNC8 αβ can potentially be developed into an effective and safe antiviral agent that targets the lipid compartments of viral envelopes of extracellular virions, more or less independent of virus antigenic mutations, which faces many antiviral drugs and vaccines.
急需有效的广谱抗病毒药物来对抗现有和新出现的病毒感染。考虑到疫苗的开发是一个昂贵且耗时的过程，而且病毒不断突变使疫苗失效，这一点尤为重要。抗菌肽 (AMP)，如细菌素，是作为针对包膜病毒的抗病毒药物的有吸引力的候选物。其中一种细菌素是 PLNC8 αβ，它由带正电荷的两亲性肽组成，对包括病毒包膜中的富含磷酰丝氨酸的脂质膜在内的带负电荷的病原体膜结构具有高亲和力。由于病毒包膜与宿主细胞膜在形态和生理上存在差异，PLNC8 αβ 被认为具有很高的安全性，因为它专门针对病毒包膜而不会影响宿主细胞膜。在这项研究中，我们已经测试了 PLNC8 αβ 对黄病毒 Langat 和 Kunjin、冠状病毒 SARS-CoV-2、甲型流感病毒 (IAV) 和人类免疫缺陷病毒-1 (HIV-1) 的抗病毒作用。消除所有感染性病毒颗粒所需的 PLNC8 αβ 浓度在纳摩尔 (nM) 到微摩尔 (μM) 范围内，考虑到其脂质包膜中胆固醇含量较高 (8-35%)，这是非常有效的。我们发现，在 ER/Golgi 复合体中复制的病毒，例如 SARS-CoV-2 和黄病毒，比从质膜获得其脂质包膜的病毒，例如 IAV 和 HIV-1，对 PLNC8 αβ 更为敏感。开发新型广谱抗病毒药物可以通过快速有效地消除感染性病毒粒子，从而限制病毒在个体之间的传播和扩散，显著有益于人类健康。PLNC8 αβ 有可能成为一种有效的、安全的抗病毒药物，针对细胞外病毒粒子包膜的脂质区室，或多或少独立于病毒抗原突变，这是许多抗病毒药物和疫苗所面临的问题。
