Screening of Compounds to Increase Hemoglobin- Oxygen Affinity for Therapeutic Purposes

• Grant number: 22/15313-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2023
• End date: April 30, 2024
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Susan Elisabeth Domingues Costa Jorge
• Grantee: Diogo Grangnani Lopes
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 19/18886-1 - Pathophysiological mechanisms and treatment of red blood cell abnormalities, AP.TEM

Abstract

Hemoglobin (Hb) is a tetramer hemeprotein found in high concentrations in erythrocytes, formed by a pair of ±-like chains and a pair of ²-like chains, each associated with a heme prosthetic group with a ferrous atom capable of reversibly binding. to oxygen. The HbO2 binding is mediated by several mechanisms, such as O2 pressure (PO2), H+/CO2 and 2,3-bisphosphoglycerate (2,3-BPG) and represented by the oxygen dissociation curve (ODC). Affinity can be altered by some substances, pH (Bohr effect) or conditions that cause hypoxemia, such as Acute Respiratory Distress Syndrome (ARDS - acute lung inflammation). Respiratory diseases such as COVID-19 can lead to ARDS with significant mortality, in addition to exorbitant expenses for treatment with hospitalizations. The use of compounds that increase HbO2 affinity may be a therapeutic alternative for these cases of lung diseases. The ²Asp99 region at the ±1²2 interface can be studied, since small changes in this location cause an increase in the affinity of Hb for O2. Some compounds like 5-hydroxymethyl-2-furfural (5-HMF), di(5-(2,3-dihydro-1,4-benzodioxin-2-yl)-4H-1,2,4-triazol-3- yl)disulfide (TD-1) and voxelotor have the ability to shift ODC to the left, increasing HbO2 affinity. These changes in ODC are important as they significantly alter arterial oxygen content. This project aims to investigate the potential increase in hemoglobin affinity for oxygen promoted by the compounds already mentioned and described in the literature, in addition to screening two others by in silico techniques. The screening of compounds will be carried out in collaboration with the laboratory coordinated by Prof. Flávio Seixas, from the State University of Maringá, specialist in studies and Compound Screening and Docking, and the researcher Érica Prates, from Oack Ridge National Laboratory, TN, USA, specialist in Docking e Molecular Dinamics Simulation. Selected compounds must be submitted to a dosage and toxicity study, in addition to a functional study of Hb, from equilibrium curves of Hb-O2 binding, at pHs 6.5, 7.5 and 8.0 for calculations of Bohr effect and heme-heme cooperativeness. It is hoped that with this work it will be possible to prospect potential compounds for future application in clinical cases with lower O2 bioavailability, such as hypoxemia (with and without changes in blood pH, which hinder Hb-ligand binding) in order to improve the efficiency of Hb-O2 binding, providing greater comfort to patients, reduction of invasive interventions or even the length of hospital stay, being a potential adjuvant in the treatment of patients diagnosed with ARDS.