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In a proof-of-concept study, we successfully incorporated nitrate ester groups onto two previously studied potent antisickling aromatic aldehydes, TD7 and VZHE039, to form TD7-NO and VZHE039-NO hybrids, respectively. These compounds are stable in buffer but demonstrated the expected release of NO in whole blood in vitro and in mice. The more promising VZHE039-NO retained the functional and antisickling activities of the parent VZHE039 molecule. Moreover, VZHE039-NO, unlike VZHE039, significantly attenuated RBC adhesion to laminin, suggesting this compound has potential in vivo RBC anti-adhesion properties relevant to vaso-occlusive events. Crystallographic studies show that, as with VZHE039, VZHE039-NO also binds to liganded Hb to make similar protein interactions. The knowledge gained during these investigations provides a unique opportunity to generate a superior candidate drug in SCD with enhanced benefits.<\/jats:p>","DOI":"10.3390\/molecules27206835","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T22:45:29Z","timestamp":1665614729000},"page":"6835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Boshi","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohini S.","family":"Ghatge","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2563-3002","authenticated-orcid":false,"given":"Akua K.","family":"Donkor","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faik N.","family":"Musayev","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanvi M.","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Vertex Pharmaceutical Incorporated, Boston, MA 02210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1126-5886","authenticated-orcid":false,"given":"Mohammed","family":"Al-Awadh","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rana T.","family":"Alhashimi","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Health System, Durham NC 27710, USA"},{"name":"Department of Medicine, Durham VA Health Care System, Durham NC 27705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9825-3465","authenticated-orcid":false,"given":"Abdelsattar M.","family":"Omar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilyn J.","family":"Telen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Health System, Durham NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3404-3223","authenticated-orcid":false,"given":"Tim J.","family":"McMahon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Health System, Durham NC 27710, USA"},{"name":"Department of Medicine, Durham VA Health Care System, Durham NC 27705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osheiza","family":"Abdulmalik","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9536-1743","authenticated-orcid":false,"given":"Martin K.","family":"Safo","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.hoc.2013.11.001","article-title":"Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin","volume":"28","author":"Safo","year":"2014","journal-title":"Hematol. 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