2014 Research Highlights

Mutations in HIV-1 reverse transcriptase affect the errors made in a single cycle of viral replication

Drug resistant forms of reverse transcriptase are shown to cause an unusual pattern of errors during viral replication.

Abram ME, Ferris AL, Das K, Quinoñes O, Shao W, Tuske S, Alvord WG, Arnold E, Hughes SH. J Virol 88, 7589-601 (2014).

PubMed PMID: 24760888

PubMed Central PMCID: PMC4054409

Antiviral drugs specific for coronaviruses in preclinical development

Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses

Undesired versus design enzymatic cleavage of linkers for liver targeting

A novel chemical method for selective release of drug molecules is presented.

Chirapu SR, Bauman JN, Eng H, Goosen TC, Strelevitz TJ, Sinha SC, Dow RL & Finn MG. Bioorg. Med. Chem. Lett. 24, 1144-1147 (2014).

PubMed PMID: 24461291

PubMedCentral PMCID: PMC4319531

Structures of HIV-1 RT-RNA/DNA Ternary Complexes with dATP and Nevirapine Reveal Conformational Flexibility of RNA/DNA: Insights into Requirements for RNase H Cleavage

Changes in the conformation of DNA and RNA may be important in the cleavage of RNA strands by RT.

Das, K., Martinez, S. E., Bandwar, R. P., and Arnold, E., Nucleic Acids Res 42, 8125-8137 (2014).

Pubmed PMID: 24880687

Pubmed Central PMCID: PMC4081091

Virtual Screening of Integrase Inhibitors by Large Scale Binding Free Energy Calculations: The SAMPL4 Challenge

The Binding Energy Distribution Analysis Method improves discrimination of binders and nonbinders in a docking challenge of inhibitors to integrase.

Gallicchio, E., Deng, N., He, P., Wickstrom, L., Perryman, A. L., Santiago, D. N., Forli, S., Olson, A. J., and Levy, R. M., J Comput Aided Mol Des 28, 475-490 (2014).

Pubmed PMID: 24504704

Pubmed Central PMCID: PMC4137862

Advances in Targeting Nucleocapsid-Nucleic Acid Interactions in HIV-1 Therapy

The authors review approaches for fighting HIV with drugs that block the functions of nucleocapsid protein.

Garg, D. and Torbett, B. E., Virus Res. 193, 135-143 (2014).

Pubmed PMID: 25026536

Pubmed Central PMCID: PMC4252855

Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs

A new chemical scaffold has been validated for the design of HIV RNase H inhibitors.

Himmel DM, Myshankina NS, Ilina T, Van Ry A, Ho WC, Parniak MA & Arnold E. J. Mol. Biol. 426, 2617-2631 (2014).

PubMed PMID: 24840303

PubMedCentral PMCID: PMC4116331

SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors

SAMHD1 is an enzyme that cleaves the nucleotides needed for HIV replication, but is shown to be less active against nucleotide reverse transcriptase inhibitors.

Huber AD, Michailidis E, Schultz ML, Ong YT, Bloch N, Puray-Chavez MN, Leslie  MD, Ji J, Lucas AD, Kirby KA, Landau NR, Sarafianos SG. Antimicrob Agents Chemother 58, 4915-9 (2014).

PubMed PMID: 24867973

PubMed Central PMCID: PMC4136039

Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2

Molecular Mechanisms of Retroviral Integration Site Selection

HDX-MS guided drug discovery: small molecules and biopharmaceuticals

HIVE Center researchers review methods for integrating HDX-MS into drug discovery programs.

Marciano DP, Dharmarajan V & Griffin PR. Curr Op Struct Biol 28, 105-111 (2014)

PubMed PMID: 25179005

PubMed Central PMCID: PMC4253076

4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine (Efda) Inhibits Hiv-1 Reverse Transcriptase with Multiple Mechanisms

Blind Prediction of HIV Integrase Binding from the SAMPL4 Challenge

Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) using pre-steady-state kinetics

The inhibitor EFdA is added to a growing DNA chain by reverse transcriptase, then slows further extension of the DNA chain.

Muftuoglu Y, Sohl CD, Mislak AC, Mitsuya H, Sarafianos SG, Anderson KS. Antiviral Res 106, 1-4 (2014).

PubMed PMID: 24632447

PubMed Central PMCID: PMC4020981

Ruthenium-catalyzed cycloaddition of 1-haloalkynes with nitrile oxides and organic azides; Synthesis of 4-halo isoxazoles and 5-halo triazoles

A new method is presented for inhibitor synthesis using click chemistry.

Oakdale JS, Sit RK & Fokin VV. Chemistry 20, 11101-11110 (2014)

PubMed PMID: 25059647

PubMedCentral PMCID:PMC4442801

Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery

The authors review a powerful method for using crystallography to discover new inhibitors.

Patel D, Bauman JD, Arnold E. Prog Biophys Mol Biol 116, 92-100 (2014).

PubMed PMID: 25117499

PubMedCentral PMCID: PMC4501029

Virtual Screening with AutoDock Vina and the Common Pharmacophore Engine of a Low Diversity Library of Fragments and Hits against the Three Allosteric Sites of HIV Integrase: Participation in the SAMPL4 Protein-Ligand Binding Challenge

Phenyl substituted 4-hydroxypyridazine-3(2H)-ones and 5-hydroxypyridazin-4(3H)-ones: inhibitors of influenza A endonuclease

Inhibitors are tuned for action against influenza virus.

Sagong HY, Bauman JD, Patel D, Das K, Arnold E & Lavoie EJ. J. Med. Chem. 57, 8086-8098 (2014).

PubMed PMID: 25225968

PubMedCentral PMCID: PMC4191602

The P66 Immature Precursor of HIV-1 Reverse Transcriptase

A Critical Role of the C-Terminal Segment for Allosteric Inhibitor-Induced Aberrant Multimerization of HIV-1 Integrase

Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors

HIVE members review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes.

Singh, K., Flores, J. A., Kirby, K. A., Neogi, U., Sonnerborg, A., Hachiya, A., Das, K., Arnold, E., McArthur, C., Parniak, M., and Sarafianos, S. G., Viruses 6, 3535-3562 (2014).

Pubmed PMID: 25254383

Pubmed Central PMCID: PMC4189038

The Mechanism of H171T Resistance Reveals the Importance of N Inverted Question Mark -Protonated His171 for the Binding of Allosteric Inhibitor Bi-D to HIV-1 Integrase

Crystallographic Fragment-Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease

Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations

Computational analysis gives new insight into the dynamic coupling of subdomains in RT, and their implications for drug resistance.

Vijayan RSK, Arnold E & Das K. Proteins 82, 815-829 (2014).

PubMed PMID: 24174331

PubMedCentral PMCID: PMC4502926

Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells

Potential treatments for HIV infection using genetically-modified hematopoietic stem cells may be enhanced with rapamycin.

Wang CX, Sather BD, Wang X, Adair J, Khan I, Singh S, Lang S, Adams A, Curinga G, Kiem HP, Miao CH, Rawlings DJ & Torbett BE. Blood 124, 913-923 (2014)

PubMed PMID: 24914132

PubMed Central PMCID: PMC4126331