Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy
<b>Background:</b> The potentiator VX-770 (ivacaftor) has been approved as a monotherapy for over 95 cystic fibrosis (CF)-causing variants associated with gating/conductance defects of the CF transmembrane conductance regulator (CFTR) channel. However, despite its therapeutic success, VX...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/13/1/82 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588990610407424 |
|---|---|
| author | Mafalda Bacalhau Filipa C. Ferreira Marcelo Folhadella M. F. Azevedo Talita P. Rosa Camilla D. Buarque Miquéias Lopes-Pacheco |
| author_facet | Mafalda Bacalhau Filipa C. Ferreira Marcelo Folhadella M. F. Azevedo Talita P. Rosa Camilla D. Buarque Miquéias Lopes-Pacheco |
| author_sort | Mafalda Bacalhau |
| collection | DOAJ |
| description | <b>Background:</b> The potentiator VX-770 (ivacaftor) has been approved as a monotherapy for over 95 cystic fibrosis (CF)-causing variants associated with gating/conductance defects of the CF transmembrane conductance regulator (CFTR) channel. However, despite its therapeutic success, VX-770 only partially restores CFTR activity for many of these variants, indicating they may benefit from the combination of potentiators exhibiting distinct mechanisms of action (i.e., co-potentiators). We previously identified <b>LSO-24</b>, a hydroxy-1,2,3-triazole-based compound, as a modest potentiator of p.Arg334Trp-CFTR, a variant with a conductance defect for which no modulator therapy is currently approved. <b>Objective/Methods:</b> We synthesized a new set of LSO-24 structure-based compounds, screened their effects on p.Arg334Trp-CFTR activity, and assessed the additivity of hit compounds to VX-770, ABBV-974, ABBV-3067, and apigenin. After validation by electrophysiological assays, the most promising hits were also assessed in cells expressing other variants with defective gating/conductance, namely p.Pro205Ser, p.Ser549Arg, p.Gly551Asp, p.Ser945Leu, and p.Gly1349Asp. <b>Results:</b> We found that five compounds were able to increase p.Arg334Trp-CFTR activity with similar efficacy, but slightly greater potency promoted by LSO-150 and LSO-153 (EC<sub>50</sub>: 1.01 and 1.26 μM, respectively). These two compounds also displayed a higher rescue of p.Arg334Trp-CFTR activity in combination with VX-770, ABBV-974, and ABBV-3067, but not with apigenin. When tested in cells expressing other CFTR variants, LSO-24 and its derivative LSO-150 increased CFTR activity for the variants p.Ser549Arg, p.Gly551Asp, and p.Ser945Leu with a further effect in combination with VX-770 or ABBV-3067. No potentiator was able to rescue CFTR activity in p.Pro205Ser-expressing cells, while p.Gly1349Asp-CFTR responded to VX-770 and ABBV-3067 but not to LSO-24 or LSO-150. <b>Conclusions:</b> Our data suggest that these new potentiators might share a common mechanism with apigenin, which is conceivably distinct from that of VX-770 and ABBV-3067. The additive rescue of p.Arg334Trp-, p.Ser549Arg-, p.Gly551Asp-, and p.Ser945Leu-CFTR also indicates that these variants could benefit from the development of a co-potentiator therapy. |
| format | Article |
| id | doaj-art-8de76f935606479aaf3ba428973d2c52 |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-8de76f935606479aaf3ba428973d2c522025-01-24T13:23:57ZengMDPI AGBiomedicines2227-90592025-01-011318210.3390/biomedicines13010082Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator TherapyMafalda Bacalhau0Filipa C. Ferreira1Marcelo Folhadella M. F. Azevedo2Talita P. Rosa3Camilla D. Buarque4Miquéias Lopes-Pacheco5Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, PortugalBiosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, PortugalDepartment of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22541-041, BrazilDepartment of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22541-041, BrazilDepartment of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22541-041, BrazilBiosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal<b>Background:</b> The potentiator VX-770 (ivacaftor) has been approved as a monotherapy for over 95 cystic fibrosis (CF)-causing variants associated with gating/conductance defects of the CF transmembrane conductance regulator (CFTR) channel. However, despite its therapeutic success, VX-770 only partially restores CFTR activity for many of these variants, indicating they may benefit from the combination of potentiators exhibiting distinct mechanisms of action (i.e., co-potentiators). We previously identified <b>LSO-24</b>, a hydroxy-1,2,3-triazole-based compound, as a modest potentiator of p.Arg334Trp-CFTR, a variant with a conductance defect for which no modulator therapy is currently approved. <b>Objective/Methods:</b> We synthesized a new set of LSO-24 structure-based compounds, screened their effects on p.Arg334Trp-CFTR activity, and assessed the additivity of hit compounds to VX-770, ABBV-974, ABBV-3067, and apigenin. After validation by electrophysiological assays, the most promising hits were also assessed in cells expressing other variants with defective gating/conductance, namely p.Pro205Ser, p.Ser549Arg, p.Gly551Asp, p.Ser945Leu, and p.Gly1349Asp. <b>Results:</b> We found that five compounds were able to increase p.Arg334Trp-CFTR activity with similar efficacy, but slightly greater potency promoted by LSO-150 and LSO-153 (EC<sub>50</sub>: 1.01 and 1.26 μM, respectively). These two compounds also displayed a higher rescue of p.Arg334Trp-CFTR activity in combination with VX-770, ABBV-974, and ABBV-3067, but not with apigenin. When tested in cells expressing other CFTR variants, LSO-24 and its derivative LSO-150 increased CFTR activity for the variants p.Ser549Arg, p.Gly551Asp, and p.Ser945Leu with a further effect in combination with VX-770 or ABBV-3067. No potentiator was able to rescue CFTR activity in p.Pro205Ser-expressing cells, while p.Gly1349Asp-CFTR responded to VX-770 and ABBV-3067 but not to LSO-24 or LSO-150. <b>Conclusions:</b> Our data suggest that these new potentiators might share a common mechanism with apigenin, which is conceivably distinct from that of VX-770 and ABBV-3067. The additive rescue of p.Arg334Trp-, p.Ser549Arg-, p.Gly551Asp-, and p.Ser945Leu-CFTR also indicates that these variants could benefit from the development of a co-potentiator therapy.https://www.mdpi.com/2227-9059/13/1/82CFTR modulatorcystic fibrosisdrug developmentpotentiatorrare mutationR334W |
| spellingShingle | Mafalda Bacalhau Filipa C. Ferreira Marcelo Folhadella M. F. Azevedo Talita P. Rosa Camilla D. Buarque Miquéias Lopes-Pacheco Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy Biomedicines CFTR modulator cystic fibrosis drug development potentiator rare mutation R334W |
| title | Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy |
| title_full | Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy |
| title_fullStr | Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy |
| title_full_unstemmed | Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy |
| title_short | Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy |
| title_sort | rescue of mutant cftr channel activity by investigational co potentiator therapy |
| topic | CFTR modulator cystic fibrosis drug development potentiator rare mutation R334W |
| url | https://www.mdpi.com/2227-9059/13/1/82 |
| work_keys_str_mv | AT mafaldabacalhau rescueofmutantcftrchannelactivitybyinvestigationalcopotentiatortherapy AT filipacferreira rescueofmutantcftrchannelactivitybyinvestigationalcopotentiatortherapy AT marcelofolhadellamfazevedo rescueofmutantcftrchannelactivitybyinvestigationalcopotentiatortherapy AT talitaprosa rescueofmutantcftrchannelactivitybyinvestigationalcopotentiatortherapy AT camilladbuarque rescueofmutantcftrchannelactivitybyinvestigationalcopotentiatortherapy AT miqueiaslopespacheco rescueofmutantcftrchannelactivitybyinvestigationalcopotentiatortherapy |