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).
Antiviral drugs specific for coronaviruses in preclinical development
This review describes new inhibitors for SARS and MERS coronaviruses.
Adedeji AO, Sarafianos SG. Curr Opin Virol 8, 45-53 (2014).
Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses
An inhibitor has been discovered that inhibits replication of three coronaviruses.
Adedeji AO, Singh K, Kassim A, Coleman CM, Elliott R, Weiss SR, Frieman MB, Sarafianos SG. Antimicrob Agents Chemother 58, 4894-8 (2014).
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).
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).
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).
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).
Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2
The structure of the envelope glycoprotein of hepatitis C virus provides a new target for development of inhibitors and vaccines.
Khan AG, Whidby J, Miller MT, Scarborough H, Zatorski AV, Cygan A, Price AA, Yost SA, Bohannon CD, Jacob J, Grakoui A, Marcotrigiano J. Nature 509, 381-4 (2014).
Molecular Mechanisms of Retroviral Integration Site Selection
HIVE researchers review the process of site selection in retroviral integration.
Kvaratskhelia, M., Sharma, A., Larue, R. C., Serrao, E., and Engelman, A., Nucleic Acids Res 42, 10209-10225 (2014).
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
EFdA blocks HIV RT by several mechanisms, making it an effective antiviral agent with a favorable resistance profile.
Michailidis, E., Huber, A. D., Ryan, E. M., Ong, Y. T., Leslie, M. D., Matzek, K. B., Singh, K., Marchand, B., Hagedorn, A. N., Kirby, K. A., Rohan, L. C., Kodama, E. N., Mitsuya, H., Parniak, M. A., and Sarafianos, S. G., J Biol Chem 289, 24533-24548 (2014).
Blind Prediction of HIV Integrase Binding from the SAMPL4 Challenge
Results from a docking challenge for inhibitors to integrase are reviewed.
Mobley, D. L., Liu, S., Lim, N. M., Wymer, K. L., Perryman, A. L., Forli, S., Deng, N., Su, J., Branson, K., and Olson, A. J., J Comput Aided Mol Des 28, 327-345 (2014).
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).
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)
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).
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
HIVE members perform well in a docking challenge to predict the binding of inhibitors to integrase.
Perryman, A. L., Santiago, D. N., Forli, S., Santos-Martins, D., and Olson, A. J., J Comput Aided Mol Des 28, 429-441 (2014).
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
NMR experiments reveal the mechanism of RT maturation.
Sharaf, N. G., Poliner, E., Slack, R. L., Christen, M. T., Byeon, I. J., Parniak, M. A., Gronenborn, A. M., and Ishima, R., Proteins 82, 2343-2352 (2014).
A Critical Role of the C-Terminal Segment for Allosteric Inhibitor-Induced Aberrant Multimerization of HIV-1 Integrase
Mass spectrometry-based protein footprinting reveals that the C-terminal segment of integrase is important in multimerization by ALLINIs.
Shkriabai, N., Dharmarajan, V., Slaughter, A., Kessl, J. J., Larue, R. C., Feng, L., Fuchs, J. R., Griffin, P. R., and Kvaratskhelia, M., J Biol Chem 289, 26430-26440 (2014).
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).
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
The atomic basis of ALLINI resistance is revealed by crystallography.
Slaughter, A., Jurado, K. A., Deng, N., Feng, L., Kessl, J. J., Shkriabai, N., Larue, R. C., Fadel, H. J., Patel, P. A., Jena, N., Fuchs, J. R., Poeschla, E., Levy, R. M., Engelman, A., and Kvaratskhelia, M., Retrovirology 11, 100 (2014).
Crystallographic Fragment-Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease
Brominated compounds are used to determine the position of small molecules bound to the HIV protease exosites.
Tiefenbrunn, T., Forli, S., Happer, M., Gonzalez, A., Tsai, Y., Soltis, M., Elder, J. H., Olson, A. J., and Stout, C. D., Chem Biol Drug Des 83, 141-148 (2014).
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