6XVF

Crystal structure of bovine cytochrome bc1 in complex with tetrahydro-quinolone inhibitor JAG021

Summary for 6XVF

• Entry DOI: 10.2210/pdb6xvf/pdb
• Descriptor: Cytochrome b-c1 complex subunit 1, mitochondrial, Cytochrome b-c1 complex subunit 9, TETRAETHYLENE GLYCOL, ... (22 entities in total)
• Functional Keywords: cytochrome bc1, malaria, electron transport, membrane protein
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 10
• Total formula weight: 238215.60

Authors

Amporndanai, K.,Hasnain, S.S.,Antonyuk, S.V. (deposition date: 2020-01-21, release date: 2020-07-22, Last modification date: 2024-01-24)

Primary citation

McPhillie, M.J.,Zhou, Y.,Hickman, M.R.,Gordon, J.A.,Weber, C.R.,Li, Q.,Lee, P.J.,Amporndanai, K.,Johnson, R.M.,Darby, H.,Woods, S.,Li, Z.H.,Priestley, R.S.,Ristroph, K.D.,Biering, S.B.,El Bissati, K.,Hwang, S.,Hakim, F.E.,Dovgin, S.M.,Lykins, J.D.,Roberts, L.,Hargrave, K.,Cong, H.,Sinai, A.P.,Muench, S.P.,Dubey, J.P.,Prud'homme, R.K.,Lorenzi, H.A.,Biagini, G.A.,Moreno, S.N.,Roberts, C.W.,Antonyuk, S.V.,Fishwick, C.W.G.,McLeod, R.
Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.
Front Cell Infect Microbiol, 10:203-203, 2020

PubMed Abstract: Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces tachyzoites and encysted bradyzoites , and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant . Causal prophylaxis and radical cure are achieved after sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

PubMed: 32626661
DOI: 10.3389/fcimb.2020.00203

Experimental method

X-RAY DIFFRACTION (3.5 Å)