Micaela Fornabaio
Virginia Commonwealth University
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Publication
Featured researches published by Micaela Fornabaio.
Journal of Virology | 2007
Matteo Porotto; Micaela Fornabaio; Glen E. Kellogg; Anne Moscona
ABSTRACT The hemagglutinin-neuraminidase (HN) protein of paramyxoviruses carries out three discrete activities that each affect the ability of HN to promote viral fusion and entry: receptor binding, receptor cleaving (neuraminidase), and triggering of the fusion protein. The interrelationship between the receptor binding and fusion-triggering functions of HN has not been clear. For human parainfluenza type 3 (HPIV3), one bifunctional site on HN can carry out both receptor binding and neuraminidase activities, and this sites receptor binding can be inhibited by the small receptor analog zanamivir. We now report experimental evidence, complemented by computational data, for a second receptor binding site near the HPIV3 HN dimer interface. This second binding site can mediate receptor binding even in the presence of zanamivir, and it differs from the second receptor binding site of the paramyxovirus Newcastle disease virus in its function and its relationship to the primary binding site. This second binding site of HPIV3 HN is involved in triggering F. We suggest that the two receptor binding sites on HPIV3 HN each contribute in distinct ways to virus-cell interaction; one is the multifunctional site that contains both binding and neuraminidase activities, and the other contains binding activity and also is involved in fusion promotion.
Journal of Virology | 2006
Matteo Porotto; Micaela Fornabaio; Olga Greengard; Matthew Murrell; Glen E. Kellogg; Anne Moscona
ABSTRACT The hemagglutinin-neuraminidase (HN) protein of paramyxoviruses carries out three different activities: receptor binding, receptor cleaving (neuraminidase), and triggering of the fusion protein. These three discrete properties each affect the ability of HN to promote viral fusion and entry. For human parainfluenza type 3, one bifunctional site on HN can carry out both binding and neuraminidase, and the receptor mimic, zanamivir, impairs viral entry by blocking receptor binding. We report here that for Newcastle disease virus, the HN receptor avidity is increased by zanamivir, due to activation of a second site that has higher receptor avidity. Only certain receptor mimics effectively activate the second site (site II) via occupation of site I; yet without activation of this second site, binding is mediated entirely by site I. Computational modeling designed to complement the experimental approaches suggests that the potential for small molecule receptor mimics to activate site II, upon binding to site I, directly correlates with their predicted strengths of interaction with site I. Taken together, the experimental and computational data show that the molecules with the strongest interactions with site I—zanamivir and BCX 2798—lead to the activation of site II. The finding that site II, once activated, shows higher avidity for receptor than site I, suggests paradigms for further elucidating the regulation of HN′s multiple functions in the viral life cycle.
Journal of Virology | 2006
Matteo Porotto; L. Doctor; P. Carta; Micaela Fornabaio; Olga Greengard; Glen E. Kellogg; Anne Moscona
ABSTRACT Hendra virus (HeV) is a recently identified paramyxovirus that is fatal in humans and could be used as an agent of bioterrorism. The HeV receptor-binding protein (G) is required in order for the fusion protein (F) to mediate fusion, and analysis of the triggering/activation of HeV F by G should lead to strategies for interfering with this key step in viral entry. HeV F, once triggered by the receptor-bound G, by analogy with other paramyxovirus F proteins, undergoes multistep conformational changes leading to a six-helix bundle (6HB) structure that accomplishes fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions (HRN and HRC) near the fusion peptide and the transmembrane domains, respectively. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing F, after the initial triggering step, from forming the 6HB structure that is required for fusion. HeV peptides have previously been found to be effective at inhibiting HeV fusion. However, we found that a human parainfluenza virus 3 F-peptide is more effective at inhibiting HeV fusion than the comparable HeV-derived peptide.
Journal of Biological Chemistry | 2011
Shohreh F. Farzan; Laura M. Palermo; Christine C. Yokoyama; Gianmarco Orefice; Micaela Fornabaio; Aurijit Sarkar; Glen E. Kellogg; Olga Greengard; Matteo Porotto; Anne Moscona
Paramyxoviruses, including the childhood pathogen human parainfluenza virus type 3, enter host cells by fusion of the viral and target cell membranes. This fusion results from the concerted action of its two envelope glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). The receptor-bound HN triggers F to undergo conformational changes that render it competent to mediate fusion of the viral and cellular membranes. We proposed that, if the fusion process could be activated prematurely before the virion reaches the target host cell, infection could be prevented. We identified a small molecule that inhibits paramyxovirus entry into target cells and prevents infection. We show here that this compound works by an interaction with HN that results in F-activation prior to receptor binding. The fusion process is thereby prematurely activated, preventing fusion of the viral membrane with target cells and precluding viral entry. This first evidence that activation of a paramyxovirus F can be specifically induced before the virus contacts its target cell suggests a new strategy with broad implications for the design of antiviral agents.
Journal of Medicinal Chemistry | 2004
Micaela Fornabaio; Francesca Spyrakis; Andrea Mozzarelli; Pietro Cozzini; Donald J. Abraham; Glen E. Kellogg
Current Medicinal Chemistry | 2004
Pietro Cozzini; Micaela Fornabaio; Anna Marabotti; Donald J. Abraham; Glen E. Kellogg; Andrea Mozzarelli
Journal of Medicinal Chemistry | 2003
Micaela Fornabaio; Pietro Cozzini; Andrea Mozzarelli; Donald J. Abraham; Glen E. Kellogg
European Journal of Medicinal Chemistry | 2007
Francesca Spyrakis; Alessio Amadasi; Micaela Fornabaio; Donald J. Abraham; Andrea Mozzarelli; Glen E. Kellogg; Pietro Cozzini
Bioorganic & Medicinal Chemistry | 2008
Ashutosh Tripathi; Micaela Fornabaio; Glen E. Kellogg; John T. Gupton; David A. Gewirtz; W. Andrew Yeudall; Nina E. Vega; Susan L. Mooberry
Journal of the American Chemical Society | 2004
Francesca Spyrakis; Micaela Fornabaio; Pietro Cozzini; Andrea Mozzarelli; Donald J. Abraham; Glen E. Kellogg