5KRS

HIV-1 Integrase Catalytic Core Domain in Complex with an Allosteric Inhibitor, 3-(1H-pyrrol-1-yl)-2-thiophenecarboxylic acid

Summary for 5KRS

• Entry DOI: 10.2210/pdb5krs/pdb
• Related: 5KRB
• Descriptor: Integrase, DIMETHYL SULFOXIDE, 3-pyrrol-1-ylthiophene-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: hiv-1 integrase catalytic core domain, p75/ledgf inhibitor, hydrolase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 17446.62

Authors

Patel, D.,Bauman, J.D.,Arnold, E. (deposition date: 2016-07-07, release date: 2016-09-28, Last modification date: 2024-10-23)

Primary citation

Patel, D.,Antwi, J.,Koneru, P.C.,Serrao, E.,Forli, S.,Kessl, J.J.,Feng, L.,Deng, N.,Levy, R.M.,Fuchs, J.R.,Olson, A.J.,Engelman, A.N.,Bauman, J.D.,Kvaratskhelia, M.,Arnold, E.
A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.
J.Biol.Chem., 291:23569-23577, 2016

PubMed Abstract: HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC of 72 μm and impaired HIV-1 infection of T cells at an EC of 36 μm The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structure-based development of second-generation ALLINIs.

PubMed: 27645997
DOI: 10.1074/jbc.M116.753384

Experimental method

X-RAY DIFFRACTION (1.7 Å)