Networks link antigenic and receptor-binding sites of influenza hemagglutinin: Mechanistic insight into fitter strain propagation

Soundararajan, Venkataramanan; Zheng, Shu; Patel, Neel; Warnock, Ken; Raman, Rahul; Wilson, Ian A.; Raguram, S.; Sasisekharan, V.; Sasisekharan, Ram

doi:10.1038/srep00200

Cited by 47 publications

(63 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this effort, we sought to identify an antibody targeting amino acids within the trimeric interface within the stem region of HA, which are highly networked, and therefore potentially limited in their ability to mutate (9). Using a database of nonredundant combinations of complementary determining region (CDR) canonical structures (antibody scaffolds), we selected multiple antibody templates satisfying shape complementarity criteria and systematically engineered energetically favorable, hotspot-like interactions between CDR residues and these anchor residues on HA.…”

Section: Resultsmentioning

confidence: 99%

A broadly neutralizing human monoclonal antibody is effective against H7N9

Tharakaraman

Subramanian

Viswanathan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Emerging strains of influenza represent a significant public health threat with potential pandemic consequences. Of particular concern are the recently emerged H7N9 strains which cause pneumonia with acute respiratory distress syndrome. Estimates are that nearly 80% of hospitalized patients with H7N9 have received intensive care unit support. VIS410, a human antibody, targets a unique conserved epitope on influenza A. We evaluated the efficacy of VIS410 for neutralization of group 2 influenza strains, including H3N2 and H7N9 strains in vitro and in vivo. VIS410, administered at 50 mg/kg, protected DBA mice infected with A/Anhui/2013 (H7N9), resulting in significant survival benefit upon single-dose (−24 h) or double-dose (−12 h, +48 h) administration (P < 0.001). A single dose of VIS410 at 50 mg/kg (−12 h) combined with oseltamivir at 50 mg/kg (−12 h, twice daily for 7 d) in C57BL/6 mice infected with A/Shanghai 2/2013 (H7N9) resulted in significant decreased lung viral load (P = 0.002) and decreased lung cytokine responses for nine of the 11 cytokines measured. Based on these results, we find that VIS410 may be effective either as monotherapy or combined with antivirals in treating H7N9 disease, as well as disease from other influenza strains.

show abstract

Section: Resultsmentioning

confidence: 99%

A broadly neutralizing human monoclonal antibody is effective against H7N9

Tharakaraman

Subramanian

Viswanathan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This explains the inefficient competition of GSH because cysteine is unlikely to be the main residue on the RBS region of the HA protein that interacted with Cur. W153, T155, G134, T136, H183, E190, L194, Y98, Q226 and G228 on PR8 HA protein are responsible for anchoring the SA monosaccharide, the host receptor of influenza virus [33]. Incidentally, most of these (seven out of ten) SA anchoring residues also potentially interact with Cur, as analyzed by docking simulation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structure–activity relationship analysis of curcumin analogues on anti‐influenza virus activity

Mizushina

Wang

et al. 2013

The FEBS Journal

View full text Add to dashboard Cite

Curcumin (Cur) is a commonly used colouring agent and spice in food. Previously, we reported that Cur inhibits type A influenza virus (IAV) infection by interfering with viral haemagglutination (HA) activity. To search for a stable Cur analogue with potent anti-IAV activity and to investigate the structure contributing to its anti-IAV activity, a comparative analysis of structural and functional analogues of Cur, such as tetrahydrocurcumin (THC) and petasiphenol (Pet), was performed. The result of time-of-drug addition tests indicated that these curcuminoids were able to inhibit IAV production in cell cultures. Noticeably, Pet and THC inhibit IAV to a lesser extent than Cur, which is in line with their effect on reducing plaque formation when IAV was treated with Cur analogues before infection. Unexpectedly, both THC and Pet did not harbour any HA inhibitory effect. It should be noted that the structure of Pet and THC differs from Cur with respect to the number of double bonds present in the central seven-carbon chain, and structure modelling of Cur analogues indicates that the conformations of THC and Pet are distinct from that of Cur. Moreover, simulation docking of Cur with the HA structure revealed that Cur binds to the region constituting sialic acid anchoring residues, supporting the results obtained by the inhibition of HA activity assay. Collectively, structure-activity relationship analyses indicate that the presence of the double bonds in the central seven-carbon chain enhanced the Cur -dependent anti-IAV activity and also that Cur might interfere with IAV entry by its interaction with the receptor binding region of viral HA protein.

show abstract

“…Other than S185T, present in all 76 sequences, A186T, present in the single Quebec sequence, and possibly N156K and S157L [22], each present in a single and different Alberta sequence, none of the other substitutions were located within or adjacent to the receptor-binding site. With the exception of the single Quebec sequence, antigenic site mutations R205K, A141T, and A186T, which are located close to the receptor-binding site [22][23][24][25] and which occurred in 37%, 30% and 14%, respectively, of sentinel sequences during the 2012/13 season [21], were not evident in 2013/14.…”

Section: Virus Characterisationmentioning

confidence: 99%