4ZTF
Crystal Structure of the Prototype Foamy Virus Intasome with a 2-Pyridinone Aminal Inhibitor
Summary for 4ZTF
| Entry DOI | 10.2210/pdb4ztf/pdb |
| Descriptor | Integrase, 19 NUCLEOTIDE PREPROCESSED PFV DONOR DNA (NON-TRANSFERRED STRAND), 17 NUCLEOTIDE PREPROCESSED PFV DONOR DNA (TRANSFERRED STRAND), ... (9 entities in total) |
| Functional Keywords | transferase-dna complex, dna integration, viral protein, recombination-inhibitor-dna complex, transferase-dna-inhibitor complex, transferase/dna/inhibitor |
| Biological source | Human spumaretrovirus (SFVcpz(hu)) More |
| Cellular location | Integrase: Virion . Protease/Reverse transcriptase/ribonuclease H: Host nucleus : P14350 |
| Total number of polymer chains | 4 |
| Total formula weight | 101240.41 |
| Authors | Klein, D.J.,Patel, S. (deposition date: 2015-05-14, release date: 2015-10-07, Last modification date: 2024-03-06) |
| Primary citation | Raheem, I.T.,Walji, A.M.,Klein, D.,Sanders, J.M.,Powell, D.A.,Abeywickrema, P.,Barbe, G.,Bennet, A.,Clas, S.D.,Dubost, D.,Embrey, M.,Grobler, J.,Hafey, M.J.,Hartingh, T.J.,Hazuda, D.J.,Miller, M.D.,Moore, K.P.,Pajkovic, N.,Patel, S.,Rada, V.,Rearden, P.,Schreier, J.D.,Sisko, J.,Steele, T.G.,Truchon, J.F.,Wai, J.,Xu, M.,Coleman, P.J. Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors. J.Med.Chem., 58:8154-8165, 2015 Cited by PubMed Abstract: The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules. PubMed: 26397965DOI: 10.1021/acs.jmedchem.5b01037 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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