3-Hydroxypyrimidine-2,4-diones as an inhibitor scaffold of HIV integrase.

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.

[1]  Philippe Cotelle,et al.  Patented HIV-1 integrase inhibitors (1998-2005). , 2006, Recent patents on anti-infective drug discovery.

[2]  Y. Pommier,et al.  N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase. , 2011, ACS medicinal chemistry letters.

[3]  S. Piscitelli,et al.  Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers , 2009, Antimicrobial Agents and Chemotherapy.

[4]  A. Engelman,et al.  Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. , 1994, Science.

[5]  A. Engelman.  Host cell factors and HIV-1 integration , 2007 .

[6]  R. Shoemaker,et al.  β-Diketo Acid Pharmacophore Hypothesis. 1. Discovery of a Novel Class of HIV-1 Integrase Inhibitors , 2005 .

[7]  K. Danel,et al.  Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. , 1996, Journal of medicinal chemistry.

[8]  Myriam Witvrouw,et al.  Pharmacophore-based design of HIV-1 integrase strand-transfer inhibitors. , 2005, Journal of medicinal chemistry.

[9]  R T Walker,et al.  Synthesis and antiviral activity of deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. , 1992, Journal of medicinal chemistry.

[10]  Robert Craigie,et al.  HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer , 1991, Cell.

[11]  Myriam Witvrouw,et al.  Virus Evolution Reveals an Exclusive Role for LEDGF/p75 in Chromosomal Tethering of HIV , 2007, PLoS pathogens.

[12]  N. Prada,et al.  Novel integrase inhibitors for HIV , 2010, Expert opinion on investigational drugs.

[13]  C. Monneret,et al.  Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). , 1997, Journal of medicinal chemistry.

[14]  R. Dayam,et al.  Diketo acid pharmacophore. 2. Discovery of structurally diverse inhibitors of HIV-1 integrase. , 2005, Journal of medicinal chemistry.

[15]  M A Nowak,et al.  Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Engelman,et al.  Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p 75 , 2005 .

[17]  D. Hazuda,et al.  Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. , 2008, Journal of medicinal chemistry.

[18]  R. Craigie,et al.  HIV integrase structure and function. , 1999, Advances in virus research.

[19]  Y. Pommier,et al.  Preferential Inhibition of the Magnesium-Dependent Strand Transfer Reaction of HIV-1 Integrase by α-Hydroxytropolones , 2006, Molecular Pharmacology.

[20]  B. Masquelier,et al.  HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. , 2010, The Journal of antimicrobial chemotherapy.

[21]  A. Engelman,et al.  Retroviral intasome assembly and inhibition of DNA strand transfer , 2010, Nature.

[22]  O. Bagasra.  A unified concept of HIV latency , 2006, Expert opinion on biological therapy.

[23]  A. Engelman,et al.  Structure-based modeling of the functional HIV-1 intasome and its inhibition , 2010, Proceedings of the National Academy of Sciences.

[24]  P. Yeni.  Update on HAART in HIV. , 2006, Journal of hepatology.

[25]  R. Stroud,et al.  Catalytically-active complex of HIV-1 integrase with a viral DNA substrate binds anti-integrase drugs , 2009, Proceedings of the National Academy of Sciences.

[26]  S. Dubey,et al.  Development of integrase inhibitors for treatment of AIDS: an overview. , 2007, European journal of medicinal chemistry.

[27]  R T Walker,et al.  Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. , 2010, Journal of medicinal chemistry.

[28]  Kazuya Shimura,et al.  Elvitegravir: A New HIV Integrase Inhibitor , 2009, Antiviral chemistry & chemotherapy.

[29]  T. Hansson,et al.  Estimation of binding free energies for HIV proteinase inhibitors by molecular dynamics simulations. , 1995, Protein engineering.

[30]  J. Briggs,et al.  Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors. , 2006, Journal of medicinal chemistry.

[31]  Y. Pommier,et al.  Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited. , 2010, Bioorganic & medicinal chemistry letters.

[32]  B. Dong,et al.  Raltegravir: the first HIV integrase inhibitor. , 2008, Clinical therapeutics.

[33]  C. Salomon,et al.  Rationally designed dual inhibitors of HIV reverse transcriptase and integrase. , 2007, Journal of medicinal chemistry.

[34]  C. Monneret,et al.  Synthesis and Anti‐HIV Activity of Novel N‐1 Side Chain‐Modified Analogues of 1‐((2‐Hydroxyethoxy)methyl)‐6‐(phenylthio)thymine (HEPT). , 1997 .

[35]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[36]  P. Tauc,et al.  Determinants of Mg2+-dependent activities of recombinant human immunodeficiency virus type 1 integrase. , 2000, Biochemistry.

[37]  Y. Pommier,et al.  Integrase inhibitors to treat HIV/Aids , 2005, Nature Reviews Drug Discovery.

[38]  C. O'brien.  HIV integrase structure catalyzes drug search. , 1994, Science.

[39]  A. Engelman,et al.  Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Maxwell D. Cummings,et al.  Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance , 2010, Proceedings of the National Academy of Sciences.

[41]  R. T. Walker,et al.  HEPT: From an Investigation of Lithiation of Nucleosides Towards a Rational Design of Non-Nucleoside Reverse Transcriptase Inhibitors of HIV-1 , 2000 .

[42]  J. Errey,et al.  Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces: versatile and switchable access to functionalized proteins. , 2008, Journal of the American Chemical Society.

[43]  Yves Pommier,et al.  Biochemical and pharmacological analyses of HIV-1 integrase flexible loop mutants resistant to raltegravir. , 2010, Biochemistry.

[44]  R Brookmeyer,et al.  Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. , 1997, Science.

[45]  Yves Pommier,et al.  HIV-1 IN inhibitors: 2010 update and perspectives. , 2009, Current topics in medicinal chemistry.

[46]  Y. Pommier,et al.  Resistance to Integrase Inhibitors , 2010, Viruses.

[47]  F. Bushman,et al.  Developing a dynamic pharmacophore model for HIV-1 integrase. , 2000, Journal of medicinal chemistry.

[48]  A. Marchand,et al.  Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. , 2010, Nature chemical biology.

[49]  D. Davies,et al.  Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Alessandro Brigo,et al.  HIV-1 integrase pharmacophore model derived from diverse classes of inhibitors. , 2004, Bioorganic & medicinal chemistry letters.