5UOQ

CRYSTAL STRUCTURE OF THE PROTOTYPE FOAMY VIRUS INTASOME WITH A 2- PYRIDINONE AMINAL INHIBITOR (COMPOUND 31)

Summary for 5UOQ

• Entry DOI: 10.2210/pdb5uoq/pdb
• Related: 5uop
• Descriptor: INTEGRASE, NUCLEOTIDE PREPROCESSED PFV DONOR DNA (NON-TRANSFERRED STRAND), 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: 101335.46

Authors

Klein, D.J. (deposition date: 2017-02-01, release date: 2017-03-29, Last modification date: 2024-03-06)

Primary citation

Schreier, J.D.,Embrey, M.W.,Raheem, I.T.,Barbe, G.,Campeau, L.C.,Dubost, D.,McCabe Dunn, J.,Grobler, J.,Hartingh, T.J.,Hazuda, D.J.,Klein, D.,Miller, M.D.,Moore, K.P.,Nguyen, N.,Pajkovic, N.,Powell, D.A.,Rada, V.,Sanders, J.M.,Sisko, J.,Steele, T.G.,Wai, J.,Walji, A.,Xu, M.,Coleman, P.J.
Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.
Bioorg. Med. Chem. Lett., 27:2038-2046, 2017

PubMed Abstract: HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

PubMed: 28285916
DOI: 10.1016/j.bmcl.2017.02.039

Experimental method

X-RAY DIFFRACTION (2.61 Å)