Skip to Content
Merck
CN
  • TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection.

TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection.

Thorax (2020-10-29)
Hayley Pearson, Eleanor J A A Todd, Mareike Ahrends, Samantha E Hover, Adrian Whitehouse, Martin Stacey, Jonathan D Lippiat, Ludwig Wilkens, Hans-Gerd Fieguth, Olga Danov, Christina Hesse, John N Barr, Jamel Mankouri
ABSTRACT

Human respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally and is one of the most fatal infectious diseases for infants in developing countries. Of those infected, 25%-40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. Evidence also suggests that HRSV infection early in life is a major cause of adult asthma. There is no HRSV vaccine, and the only clinically approved treatment is immunoprophylaxis that is expensive and only moderately effective. New anti-HRSV therapeutic strategies are therefore urgently required. It is now established that viruses require cellular ion channel functionality to infect cells. Here, we infected human lung epithelial cell lines and ex vivo human lung slices with HRSV in the presence of a defined panel of chloride (Cl-) channel modulators to investigate their role during the HRSV life-cycle. We demonstrate the requirement for TMEM16A, a calcium-activated Cl- channel, for HRSV infection. Time-of-addition assays revealed that the TMEM16A blockers inhibit HRSV at a postentry stage of the virus life-cycle, showing activity as a postexposure prophylaxis. Another important negative-sense RNA respiratory pathogen influenza virus was also inhibited by the TMEM16A-specific inhibitor T16Ainh-A01. These findings reveal TMEM16A as an exciting target for future host-directed antiviral therapeutics.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Tannic acid, ACS reagent
Sigma-Aldrich
CFTR(inh)-172, ≥98% (HPLC), powder
Sigma-Aldrich
5-Nitro-2-(3-phenylpropylamino)benzoic acid, ≥98%
Sigma-Aldrich
Protease Inhibitor Cocktail, for use in tissue culture media, DMSO solution
Sigma-Aldrich
Anti-Goat IgG (whole molecule)–Peroxidase antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Chromanol 293B, ≥98% (HPLC), powder
Sigma-Aldrich
CaCCinh-A01, ≥98% (HPLC)
Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Niflumic acid
Sigma-Aldrich
Ribavirin, antiviral
Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
R(+)-IAA-94, ≥98% (HPLC), solid
Sigma-Aldrich
MONNA, ≥98% (HPLC)
Niflumic acid, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Talniflumate, ≥98% (HPLC)