7JY3

Structure of HbA with compound 23 (PF-07059013)

7JY3 の概要

• エントリーDOI: 10.2210/pdb7jy3/pdb
• 分子名称: Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (7 entities in total)
• 機能のキーワード: hemoglobin, oxygen transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 66727.34

構造登録者

Jasti, J. (登録日: 2020-08-28, 公開日: 2021-01-13, 最終更新日: 2023-10-18)

主引用文献

Gopalsamy, A.,Aulabaugh, A.E.,Barakat, A.,Beaumont, K.C.,Cabral, S.,Canterbury, D.P.,Casimiro-Garcia, A.,Chang, J.S.,Chen, M.Z.,Choi, C.,Dow, R.L.,Fadeyi, O.O.,Feng, X.,France, S.P.,Howard, R.M.,Janz, J.M.,Jasti, J.,Jasuja, R.,Jones, L.H.,King-Ahmad, A.,Knee, K.M.,Kohrt, J.T.,Limberakis, C.,Liras, S.,Martinez, C.A.,McClure, K.F.,Narayanan, A.,Narula, J.,Novak, J.J.,O'Connell, T.N.,Parikh, M.D.,Piotrowski, D.W.,Plotnikova, O.,Robinson, R.P.,Sahasrabudhe, P.V.,Sharma, R.,Thuma, B.A.,Vasa, D.,Wei, L.,Wenzel, A.Z.,Withka, J.M.,Xiao, J.,Yayla, H.G.
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.
J.Med.Chem., 64:326-342, 2021

PubMed Abstract: Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at , a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. (PF-07059013) has advanced to phase 1 clinical trials.

PubMed: 33356244
DOI: 10.1021/acs.jmedchem.0c01518

実験手法

X-RAY DIFFRACTION (1.48 Å)