Nonpeptide Inhibitors of Measles Virus Entry

Abstract

Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500,000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head-neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-microM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6-3.0 microM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.

N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity

“…2). In this assay, MV-induced cell fusion was most efficiently inhibited with compound 1 (IC 50 53 mM; identical to compound 3g in Sun et al, 2006) followed by compound 5 (IC 50 58 mM; identical to compound AS-48), and less efficiently by compounds 3, 2 and 4. CDV-induced cell fusion was also efficiently inhibited by compounds 1 and 5 (IC 50 56 and 4 mM, respectively), whereas NiV-induced cell fusion was not inhibited in this concentration range.…”

“…1), including the MV-induced fusion inhibitor AS-48 (compound 5; compound 11f in Sun et al, 2006), using a modified method as described by Sun et al (2006) (see Methods). These compounds were tested in a cell-cell fusion assay based on the transfection of viral envelope proteins in the absence of other viral genes.…”

“…Compound 1 was assessed earlier as a derivative of an effective inhibitor of MV-induced membrane fusion (AS-48, compound 5) (Plemper et al, 2004(Plemper et al, , 2005Sun et al, 2006). Sun et al (2006) tested the activity of compound 1 (compound 3g in Sun et al, 2006) using Vero cells and an attenuated vaccine-like MV strain (Edmonston), which uses the receptor CD46 on Vero cells (Erlenhoefer et al, 2002).…”

“…Small-molecule inhibitors, fitting into a pocket of the MV F protein and preventing membrane fusion by blocking the natural interaction between the two essential heptad-repeat regions within the F protein, have been designed. They interfere with the conformational changes of the F protein at the beginning of the fusion process (Plemper et al, 2004(Plemper et al, , 2005Sun et al, 2006). Given the structural similarity of paramyxovirus F proteins, we tested some of these smallmolecule inhibitors and several derivatives in a NiV F proteinbased fusion assay (Niedermeier et al, 2009 (Fig.…”

“…We investigated other small-molecule fusion inhibitors, including N-(3-cyanophenyl)-2-phenylacetamide (compound 1; Sun et al, 2006), and describe its high capacity to inhibit MV-and CDV-induced, but not NiV-induced, membrane fusion. Compound 1 is of outstanding interest because it can be synthesized easily and its cytotoxicity is low.…”