2020同步年報

052 ACTIVITY REPORT 2020 C AMP and cGMP are second messengers that play a crit- ical role in signal transduction pathways that regulate many cellular processes. The levels of cAMP and cGMP are tightly controlled through their synthesis by nucleotidyl cy- clases and hydrolysis by cyclic nucleotide phosphodiesteras- es (PDEs). The human genome encodes 21 PDE genes that are divided into 11 families, PDE1–11, based on sequence similarity, substrate specificity and regulatory properties. Alternative splicing of mRNA or multiple promoters and transcription-starting sites further generates more than 100 PDE isoforms that vary in tissue and subcellular distribution. PDEs have been considered main therapeutic targets for a long time; numerous PDE inhibitors have been developed to treat various diseases. For example, PDE3 inhibitor milri- none and PDE4 inhibitor roflumilast are widely used to treat heart failure and particular inflammatory lung diseases, respectively. 1,2 The presence of unwanted side effects result- ing from the inability to target individual PDE isoforms is, however, the major limiting factor to success. For instance, the three first-generation PDE5 inhibitors (sildenafil, varde- nafil, tadalafil) to treat erectile dysfunction, benign prostat- ic hyperplasia and pulmonary arterial hypertension might cross-inhibit PDE1, PDE6 and PDE11 and result in visual disturbance, hearing loss and dyspepsia. 3-5 The exceptional specificity showed by FDA-proved second-generation PDE5 inhibitor avanafil is hence remarkable. 6 To understand the detailed mechanism of avanafil’s supe- rior isoform selectivity, a research team led by Nei-Li Chan (National Taiwan University) solved the crystal structure of PDE5 in a complex with avanafil by X-ray crystallography. 7 The X-ray diffraction data were collected at TLS 15A1 and TLS 13C1 of NSRRC. The final model contains the entire Fig. 1 : (a) Overall structure of the PDE5–avanafil complex. The avanafil is represented as green sticks. Mg 2+ and Zn 2+ ions are shown as green and purple spheres; sulfur and oxygen atoms of SO 4 2– are shown as brown and red spheres. (b) Chemical structure of avanafil and 2 F o – F c electron density (con- toured at 1.0 σ) for the bound avanafil. (c) Schematic diagram of interactions between avanafil and PDE5. (d) The carbonyl oxygen of A779 from helix α14 forms a halogen bond with the chlorine atom of the 3-chloro-4-methoxybenzene ring of avanafil. (e) The side chains of A779, V782 and A783 enclose a hole with the carbonyl oxygen of A779 at the bottom to accommodate the chlorine atom of avanafil. [Reproduced from Ref. 7] (a) (d) (e) (b) (c) Molecular Basis of Avanafil’s Superior Isoform Selectivity Toward Phosphodiesterase 5A1 Phosphodiesterase 5A1 (PDE5) is a key target to treat cardiovascular diseases and erectile dys- function. In this report, based on the crystal structure of the PDE5-avanafil complex, the un- derlyng mechanism of the isoform selectivity is revealed and a new concept of structure-based drug design is proposed.