Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease
5-hydroxyfurfural (5HMF), an allosteric effector of hemoglobin (Hb) with an ability to increase Hb affinity for oxygen has been studied extensively for its antisickling effect in vitro and in vivo, and in humans for the treatment of sickle cell disease (SCD). One of the downstream pathophysiologies...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/12/5/696 |
| _version_ | 1797501275879768064 |
|---|---|
| author | Rana T. Alhashimi Mohini S. Ghatge Akua K. Donkor Tanvi M. Deshpande Nancy Anabaraonye Dina Alramadhani Richmond Danso-Danquah Boshi Huang Yan Zhang Faik N. Musayev Osheiza Abdulmalik Martin K. Safo |
| author_facet | Rana T. Alhashimi Mohini S. Ghatge Akua K. Donkor Tanvi M. Deshpande Nancy Anabaraonye Dina Alramadhani Richmond Danso-Danquah Boshi Huang Yan Zhang Faik N. Musayev Osheiza Abdulmalik Martin K. Safo |
| author_sort | Rana T. Alhashimi |
| collection | DOAJ |
| description | 5-hydroxyfurfural (5HMF), an allosteric effector of hemoglobin (Hb) with an ability to increase Hb affinity for oxygen has been studied extensively for its antisickling effect in vitro and in vivo, and in humans for the treatment of sickle cell disease (SCD). One of the downstream pathophysiologies of SCD is nitric oxide (NO) deficiency, therefore increasing NO (bio)availability is known to mitigate the severity of SCD symptoms. We report the synthesis of an NO-releasing prodrug of 5HMF (5HMF-NO), which in vivo, is expected to be bio-transformed into 5HMF and NO, with concomitant therapeutic activities. In vitro studies showed that when incubated with whole blood, 5HMF-NO releases NO, as anticipated. When incubated with sickle blood, 5HMF-NO formed Schiff base adduct with Hb, increased Hb affinity for oxygen, and prevented hypoxia-induced erythrocyte sickling, which at 1 mM concentration were 16%, 10% and 27%, respectively, compared to 21%, 18% and 21% for 5HMF. Crystal structures of 5HMF-NO with Hb showed 5HMF-NO bound to unliganded (deoxygenated) Hb, while the hydrolyzed product, 5HMF bound to liganded (carbonmonoxy-ligated) Hb. Our findings from this proof-of-concept study suggest that the incorporation of NO donor group to 5HMF and analogous molecules could be a novel beneficial strategy to treat SCD and warrants further detailed in vivo studies. |
| first_indexed | 2024-03-10T03:16:03Z |
| format | Article |
| id | doaj.art-e86fec00e2774e248bc84f858cb480f1 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T03:16:03Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-e86fec00e2774e248bc84f858cb480f12023-11-23T10:14:14ZengMDPI AGBiomolecules2218-273X2022-05-0112569610.3390/biom12050696Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell DiseaseRana T. Alhashimi0Mohini S. Ghatge1Akua K. Donkor2Tanvi M. Deshpande3Nancy Anabaraonye4Dina Alramadhani5Richmond Danso-Danquah6Boshi Huang7Yan Zhang8Faik N. Musayev9Osheiza Abdulmalik10Martin K. Safo11Department of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USAVertex Pharmaceutical Incorporated, Boston, MA 02210, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USADivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Medicinal Chemistry and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA5-hydroxyfurfural (5HMF), an allosteric effector of hemoglobin (Hb) with an ability to increase Hb affinity for oxygen has been studied extensively for its antisickling effect in vitro and in vivo, and in humans for the treatment of sickle cell disease (SCD). One of the downstream pathophysiologies of SCD is nitric oxide (NO) deficiency, therefore increasing NO (bio)availability is known to mitigate the severity of SCD symptoms. We report the synthesis of an NO-releasing prodrug of 5HMF (5HMF-NO), which in vivo, is expected to be bio-transformed into 5HMF and NO, with concomitant therapeutic activities. In vitro studies showed that when incubated with whole blood, 5HMF-NO releases NO, as anticipated. When incubated with sickle blood, 5HMF-NO formed Schiff base adduct with Hb, increased Hb affinity for oxygen, and prevented hypoxia-induced erythrocyte sickling, which at 1 mM concentration were 16%, 10% and 27%, respectively, compared to 21%, 18% and 21% for 5HMF. Crystal structures of 5HMF-NO with Hb showed 5HMF-NO bound to unliganded (deoxygenated) Hb, while the hydrolyzed product, 5HMF bound to liganded (carbonmonoxy-ligated) Hb. Our findings from this proof-of-concept study suggest that the incorporation of NO donor group to 5HMF and analogous molecules could be a novel beneficial strategy to treat SCD and warrants further detailed in vivo studies.https://www.mdpi.com/2218-273X/12/5/696hemoglobinsickle cell diseaseantisicklingnitric oxideoxygen equilibrium curve |
| spellingShingle | Rana T. Alhashimi Mohini S. Ghatge Akua K. Donkor Tanvi M. Deshpande Nancy Anabaraonye Dina Alramadhani Richmond Danso-Danquah Boshi Huang Yan Zhang Faik N. Musayev Osheiza Abdulmalik Martin K. Safo Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease Biomolecules hemoglobin sickle cell disease antisickling nitric oxide oxygen equilibrium curve |
| title | Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease |
| title_full | Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease |
| title_fullStr | Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease |
| title_full_unstemmed | Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease |
| title_short | Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease |
| title_sort | design synthesis and antisickling investigation of a nitric oxide releasing prodrug of 5hmf for the treatment of sickle cell disease |
| topic | hemoglobin sickle cell disease antisickling nitric oxide oxygen equilibrium curve |
| url | https://www.mdpi.com/2218-273X/12/5/696 |
| work_keys_str_mv | AT ranatalhashimi designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT mohinisghatge designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT akuakdonkor designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT tanvimdeshpande designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT nancyanabaraonye designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT dinaalramadhani designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT richmonddansodanquah designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT boshihuang designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT yanzhang designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT faiknmusayev designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT osheizaabdulmalik designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease AT martinksafo designsynthesisandantisicklinginvestigationofanitricoxidereleasingprodrugof5hmfforthetreatmentofsicklecelldisease |