key: cord-0778934-cj0ccoed authors: Kimura, Hirokazu; Kurusu, Hiromu; Sada, Mitsuru; Kurai, Daisuke; Murakami, Koichi; Kamitani, Wataru; Tomita, Haruyoshi; Katayama, Kazuhiko; Ryo, Akihide title: Molecular pharmacology of ciclesonide against SARS-CoV-2 date: 2020-06-13 journal: J Allergy Clin Immunol DOI: 10.1016/j.jaci.2020.05.029 sha: 5cdb2394979ceafccabd82ac39e828525311e375 doc_id: 778934 cord_uid: cj0ccoed nan Molecular pharmacology of ciclesonide against SARS-CoV-2 Q 1 To the Editor: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has suddenly emerged, resulting in a pandemic. At present, there is no known safe and effective antiviral agent for COVID-19 treatment. Matsuyama et al 1 suggested that ciclesonide (Alvesco [(11b, 16a)-16, 17-[[(R)-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-pregna-1, 4-diene-3, 20-dione]), an inhaled glucocorticoid, could inhibit the replication of SARS-CoV-2 genomic RNA by targeting the viral endonuclease NSP15. However, there is no information concerning the detailed pharmacological and/or molecular mechanisms underlying this response. Here, we present an in silico study that elucidates a mechanism whereby ciclesonide might inhibit SARS-CoV-2 replication. The full-length nucleotide sequences of NSP15 and RdRp (RNA-dependent RNA polymerase) genes identified in GenBank (accession no. MN908947) were used for homology modeling. The 3-dimensional structures used for the docking simulation analysis were obtained from the PubChem database, including the structural data for nonesterified ciclesonide (compound identification [CID] number 6918155), esterified ciclesonide (desisobutyrylciclesonide [des-CIC], CID number 6918281), and fluticasone propionate (CID number 444036). Protein structure models of NSP15 and RdRp proteins (Protein Data Bank identification numbers 6VWW and 6NUR, respectively) were constructed as previously described. 2 AutoDock Vina software was used for computationally simulating the molecular recognition process (docking simulation) of the proteins and these drugs. 3 Detailed procedures of the docking simulations have been previously reported. 4 As shown in Fig 1 ½F1 , our docking simulations revealed that des-CIC could bind to the active site of NSP15 endonuclease with a binding energy of 28.5 kcal/mol. The des-CIC binding sites within NSP15 included His236, His251, Lys291, Ser295, Thr342, and Tyr344 (Fig 1) . Most of the interactions between NSP15 and des-CIC were estimated as hydrogen bonds. Similarly, nonesterified ciclesonide could also interact with activesite residues of NSP15 (27.5 kmol/mol, data not shown). In contrast, neither ciclesonide variant could bind to the active site of SARS-CoV-2 RdRp (data not shown). Moreover, fluticasone propionate, another inhaled glucocorticoid, could not bind to NSP15 or RdRp (data not shown). These results suggested that both esterified and nonesterified derivatives of ciclesonide had the capacity to interact with NSP-15, thereby possessing the capacity to inhibit replication of the SARS-CoV-2 viral genome. Nonesterified ciclesonide is metabolized by tissue esterases, resulting in des-CIC. 5 Thus, des-CIC may be the predominant form of ciclesonide in vivo. Interestingly, we found that both nonesterified ciclesonide and des-CIC were capable of interacting with NSP15, and the interaction of des-CIC with NSP15 involved the larger of the 2 predicted binding energies. As such, replication inhibition of the viral genome may relate primarily to the actions of des-CIC. However, it is critical to recognize that there is scarce information available with respect to the RNA replication mechanisms catalyzed by RdRp and NSP15. Ciclesonide is currently approved for the treatment of asthma and allergic rhinitis and has few to no adverse effects. 6, 7 Conclusively, this agent is an important candidate for consideration as potential therapy for COVID-19, and our study results may contribute to the design of other antiviral drugs against SARS-CoV-2. 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 The inhaled corticosteroid blocks coronavirus RNA replication by targeting viral NSP15 Molecular evolution of the fusion protein (F) gene in human respirovirus 3 AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading Computational protein-ligand docking and virtual drug screening with the AutoDock suite Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide Efficacy and safety of ciclesonide in the treatment of 24,037 asthmatic patients in routine medical care Efficacy and safety of ciclesonide nasal spray for the treatment of seasonal allergic rhinitis 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120