Porotto Matteo, Yokoyama Christine C, Palermo Laura M, Mungall Bruce, Aljofan Mohamad, Cortese Riccardo, Pessi Antonello, Moscona Anne
Department of Pediatrics and Department of Microbiology and Immunology, Weill Medical College of Cornell University, 515 East 71st St., New York, NY 10021, USA.
J Virol. 2010 Jul;84(13):6760-8. doi: 10.1128/JVI.00135-10. Epub 2010 Mar 31.
The fusion of enveloped viruses with the host cell is driven by specialized fusion proteins to initiate infection. The "class I" fusion proteins harbor two regions, typically two heptad repeat (HR) domains, which are central to the complex conformational changes leading to fusion: the first heptad repeat (HRN) is adjacent to the fusion peptide, while the second (HRC) immediately precedes the transmembrane domain. Peptides derived from the HR regions can inhibit fusion, and one HR peptide, T20 (enfuvirtide), is in clinical use for HIV-1. For paramyxoviruses, the activities of two membrane proteins, the receptor-binding protein (hemagglutinin-neuraminidase [HN] or G) and the fusion protein (F), initiate viral entry. The binding of HN or G to its receptor on a target cell triggers the activation of F, which then inserts into the target cell and mediates the membrane fusion that initiates infection. We have shown that for paramyxoviruses, the inhibitory efficacy of HR peptides is inversely proportional to the rate of F activation. For HIV-1, the antiviral potency of an HRC-derived peptide can be dramatically increased by targeting it to the membrane microdomains where fusion occurs, via the addition of a cholesterol group. We report here that for three paramyxoviruses-human parainfluenza virus type 3 (HPIV3), a major cause of lower respiratory tract diseases in infants, and the emerging zoonotic viruses Hendra virus (HeV) and Nipah virus (NiV), which cause lethal central nervous system diseases-the addition of cholesterol to a paramyxovirus HRC-derived peptide increased antiviral potency by 2 log units. Our data suggest that this enhanced activity is indeed the result of the targeting of the peptide to the plasma membrane, where fusion occurs. The cholesterol-tagged peptides on the cell surface create a protective antiviral shield, target the F protein directly at its site of action, and expand the potential utility of inhibitory peptides for paramyxoviruses.
包膜病毒与宿主细胞的融合由专门的融合蛋白驱动，以启动感染。“I类”融合蛋白有两个区域，通常是两个七肽重复（HR）结构域，它们对于导致融合的复杂构象变化至关重要：第一个七肽重复（HRN）与融合肽相邻，而第二个（HRC）紧接跨膜结构域之前。源自HR区域的肽可以抑制融合，一种HR肽T20（恩夫韦肽）已在临床上用于治疗HIV-1。对于副粘病毒，两种膜蛋白，即受体结合蛋白（血凝素神经氨酸酶[HN]或G）和融合蛋白（F）的活性启动病毒进入。HN或G与其在靶细胞上的受体结合会触发F的激活，然后F插入靶细胞并介导启动感染的膜融合。我们已经表明，对于副粘病毒，HR肽的抑制效力与F激活速率成反比。对于HIV-1，通过添加胆固醇基团将源自HRC的肽靶向融合发生的膜微区，可以显著提高其抗病毒效力。我们在此报告，对于三种副粘病毒——婴儿下呼吸道疾病的主要病因人副流感病毒3型（HPIV3），以及导致致命中枢神经系统疾病的新兴人畜共患病毒亨德拉病毒（HeV）和尼帕病毒（NiV）——在副粘病毒源自HRC的肽上添加胆固醇可使抗病毒效力提高2个对数单位。我们的数据表明，这种增强的活性确实是肽靶向质膜（融合发生的地方）的结果。细胞表面带有胆固醇标签的肽形成了一个保护性抗病毒屏障，直接在其作用位点靶向F蛋白，并扩展了抑制肽对副粘病毒的潜在用途。
