Benzimidazole analogs inhibit respiratory syncytial virus G protein function

Abstract

Human respiratory syncytial virus (hRSV) is a highly contagious Paramyxovirus that infects most children by age two, generating an estimated 75,000-125,000 hospitalizations in the U.S. annually. hRSV is the most common cause of bronchiolitis and pneumonia among infants and children under 1year of age, with significant mortality among high-risk groups. A regulatory agency-approved vaccine is not available, and existing prophylaxis and therapies are limited to use in high-risk pediatric patients; thus additional therapies are sorely needed. Here, we identify a series of benzimidazole analogs that inhibit hRSV infection in vitro with high potency, using a previously-reported high-throughput screening assay. The lead compound, SRI 29365 (1-[6-(2-furyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]methyl-1H-benzimidazole), has an EC50 of 66μM and a selectivity >50. We identified additional compounds with varying potencies by testing commercially-available chemical analogs. Time-of-addition experiments indicated that SRI 29365 effectively inhibits viral replication only if present during the early stages of viral infection. We isolated a virus with resistance to SRI 29365 and identified mutations in the transmembrane domain of the viral G protein genomic sequence that suggested that the compound inhibits G-protein mediated attachment of hRSV to cells. Additional experiments with multiple cell types indicated that SRI 29365 antiviral activity correlates with the binding of cell surface heparin by full-length G protein. Lastly, SRI 29365 did not reduce hRSV titers or morbidity/mortality in efficacy studies using a cotton rat model. Although SRI 29365 and analogs inhibit hRSV replication in vitro, this work suggests that the G-protein may not be a valid drug target in vivo.

Cotton rat model for testing vaccines and antivirals against respiratory syncytial virus

“…ALX-0171 demonstrated high antiviral efficacy in cotton rats when administered intranasally after RSV (strain Tracy) challenge (day 2 and/or day 3) or via nebulization 1 h before RSV challenge. 68 The clinical efficacy of ALX-0171 will be evaluated as a part of Phase II studies.…”

“…While SRI 29365 effectively inhibited viral replication in vitro, it was not effective in reducing RSV replication or associated disease in the cotton rat model, potentially suggesting that G may be a suboptimal target of RSV antivirals in vivo. 68 Studies in BALB/c mice, however, suggest that antibodies targeting RSV G protein reduce viral replication and RSV-associated pathology. 69 …”

The Co2+ Complex of [7‐Hydroxy‐4‐methyl‐8‐coumarinyl]glycine as a Nanocatalyst for the Synthesis and Biological Evaluation of New Mannich Bases of Benzimidazoles and Benzothiazoles

“…Among the various heterocyclic compounds, the benzimidazoles and benzothiazoles are of particular importance. The benzimidazoles have well known to show various biological activities and clinical applications such as anti‐inflammatory as well as analgesic activity, antifungal and antibacterial, antiviral, anthelmintic, antiproliferative, anti‐hypertensive, H3 antagonistic, human glucagon receptor antagonistic, male contraceptive and anti‐infective activities. Moreover, these molecules provide strong inhibitory effects of some important proteins such as chemokine receptor (CXCR3), interleukin 2‐inducible T cell kinase (ITK) and lymphocyte tyrosine kinase (Lck) .…”

Synthesis and Density Functional Theory Studies of Novel Heterocycle Tethered with Pyrazole and Benzimidazole Structural Motifs

“…Akin to pyrazoles, benzimidazoles have enthralled the interest of application chemist owing to varied therapeutic applications [19]. Specifically, benzimidazoles have anti-infective [20] , antiviral [21] and male contraceptive [22] activities. Benzimidazole nucleus with diverse substituents has been observed in various drugs like omeprazole, lansoprazole, pantoprazole as proton pump inhibitors, astemizole as antihistaminic, and albendazole, mebendazole, thiabendazole as antihelmintics [23,24].…”