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https://www.readbyqxmd.com/read/27907055/effect-of-glu12-his89-interaction-on-dynamic-structures-in-hiv-1-p17-matrix-protein-elucidated-by-nmr
#1
Yuta Konagaya, Rina Miyakawa, Masumi Sato, Akimasa Matsugami, Satoru Watanabe, Fumiaki Hayashi, Takanori Kigawa, Chiaki Nishimura
To test the existence of the salt bridge and stability of the HIV-1 p17 matrix protein, an E12A (mutated at helix 1) was established to abolish possible electrostatic interactions. The chemical shift perturbation from the comparison between wild type and E12A suggested the existence of an electrostatic interaction in wild type between E12 and H89 (located in helix 4). Unexpectedly, the studies using urea denaturation indicated that the E12A substitution slightly stabilized the protein. The dynamic structure of E12A was examined under physiological conditions by both amide proton exchange and relaxation studies...
2016: PloS One
https://www.readbyqxmd.com/read/27903797/accumulation-of-pol-mutations-selected-by-hla-b-52-01-c-12-02-protective-haplotype-restricted-ctls-causes-low-plasma-viral-load-due-to-low-viral-fitness-of-mutant-viruses
#2
Hayato Murakoshi, Madoka Koyanagi, Takayuki Chikata, Mohammad Arif Rahman, Nozomi Kuse, Keiko Sakai, Hiroyuki Gatanaga, Shinichi Oka, Masafumi Takiguchi
: HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population...
November 30, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27902325/targeting-naturally-occurring-epitope-variants-of-hepatitis-c-virus-with-high-affinity-t-cell-receptors
#3
Huajun Zhang, Jianbing Zhang, Lei Chen, Zhiming Weng, Ye Tian, Haifeng Zhao, Youjia Li, Lin Chen, Zhaoduan Liang, Hongjun Zheng, Wenzhuo Zhao, Shi Zhong, Yi Li
Hepatitis C virus (HCV) readily establishes chronic infection, which is characterized by failure of virus-specific CD8+ T cells. HCV uses epitope mutation and T-cell exhaustion to escape from the host immune response. Previously, we engineered high-affinity T-cell receptors (HATs) targeting HIV escape mutants. In this study, the affinity of a T-cell receptor specific for the human leukocyte antigen (HLA)-A2-restricted HCV immunodominant epitope NS3 1406-1415 (KLVALGINAV) was improved from a KD of 6.6 µM to 40 pM...
November 11, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27900665/use-of-capillary-electrophoresis-to-study-the-binding-interaction-of-aptamers-with-wild-type-k103n-and-double-mutant-k103n-y181c-hiv-1-rt-studying-the-binding-interaction-of-wild-type-k103n-and-double-mutant-k103n-y181c-hiv-1-rt-with-aptamers-by-performing
#4
Niran Aeksiri, Chompunuch Warakulwit, Supa Hannongbua, Sasimanas Unajak, Kiattawee Choowongkomon
A number of nucleic acid aptamers with high affinities to human immunodeficiency virus reverse transcriptase (HIV-1 RT) are currently known. They can potentially be developed as broad-spectrum antiviral drugs, but there is little known about their binding interaction with mutant HIV-1 RT. Therefore, we utilized non-equilibrium capillary electrophoresis of equilibrium mixture (NECEEM) to study the interaction of three HIV-1 RTs (wild type, K103N, and double mutant (K103N/Y181C)) with RT1t49 and RT12 aptamers...
November 30, 2016: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/27876849/characterization-of-two-distinct-early-post-entry-blocks-to-hiv-1-in-common-marmoset-lymphocytes
#5
Beatriz Pacheco, Luis Menéndez-Arias, Joseph Sodroski
In nature, primate lentiviruses infect humans and several Old World monkeys and apes. However, to date, lentiviruses infecting New World monkeys have not been described. We studied the susceptibility of common marmoset cells to HIV-1 infection and observed the presence of post-entry blocks to the early phase of HIV-1 infection in peripheral blood lymphocytes (PBLs) and a B lymphocytic cell line (B-LCL). The blocks present in these cells are dominant and phenotypically different from each other. In PBLs, the block occurs at the level of reverse transcription, reducing the accumulation of early and late transcripts, similar to the block imposed by TRIM5α...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27875973/structural-modifications-of-diarylpyrimidine-quinolone-hybrids-as-potent-hiv-1-nnrtis-with-an-improved-drug-resistance-profile
#6
Tian-Qi Mao, Qiu-Qin He, Wen-Xue Chen, Gang-Feng Tang, Fen-Er Chen, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque
Earlier we reported the identification of diarylpyrimidine-quinolone hybrids as a new class of HIV-1 NNRTIs. A few of these hybrids displayed moderate inhibitory activity against wt HIV-1 replication at submicromolar level, however, all of them lacked inhibitory activity against the double mutant virus (K103N/Y181C), which is the most prevalent NNRTI resistant-associated double mutant observed in the clinic. In the present study, we designed and synthesized a new series of diarylpyrimidine-quinolone hybrids featuring a halogen group at C-6' position of quinolone ring...
November 22, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27855563/novel-diaryltriazines-with-a-picolinonitrile-moiety-as-potent-hiv-1-rt-inhibitors-a-patent-evaluation-of-wo2016059647-a2
#7
Boshi Huang, Zhongxia Zhou, Dongwei Kang, Wanzhuo Li, Zihui Chen, Peng Zhan, Xinyong Liu
Diaryltriazine derivatives, which are structurally related to diarylpyrimidines, are a representative class of HIV-1 reverse transcriptase inhibitors with remarkable antiviral activities against wild-type and several mutant strains of HIV-1. A series of novel diaryltriazines with a picolinonitrile moiety was reported as potent HIV-1 RT inhibitors in the patent WO2016059647(A2). Two representative compounds 5e (hydrochloride) and 6e (hydrochloride) exhibited outstanding activities against various HIV-1 strains in cell-based assays, which were superior to those of AZT...
November 18, 2016: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27855071/high-prevalence-of-pneumocystis-jirovecii-dihydropteroate-synthase-gene-mutations-in-patients-with-first-episode-of-pneumocystis-pneumonia-in-santiago-chile-and-their-clinical-response-to-trimethoprim-sulfamethoxazole-therapy
#8
Carolina A Ponce, Magali Chabé, Claudio George, Alejandra Cárdenas, Luisa Duran, Julia Guerrero, Rebeca Bustamante, Olga Matos, Laurence Huang, Robert F Miller, Sergio L Vargas
Mutations in the Dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii associate with failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs, or be acquired via person-to-person transmission. DHPS mutations raise concern about decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with first-episode of PCP from 2002-2010 in Santiago, Chile...
November 14, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27853317/high-mannose-specific-lectin-msl-mediates-key-interactions-of-the-vaginal-lactobacillus-plantarum-isolate-cmpg5300
#9
Shweta Malik, Mariya I Petrova, Nicole C E Imholz, Tine L A Verhoeven, Sam Noppen, Els J M Van Damme, Sandra Liekens, Jan Balzarini, Dominique Schols, Jos Vanderleyden, Sarah Lebeer
To characterize the interaction potential of the human vaginal isolate Lactobacillus plantarum CMPG5300, its genome was mined for genes encoding lectin-like proteins. cmpg5300.05_29 was identified as the gene encoding a putative mannose-binding lectin. Phenotypic analysis of a gene knock-out mutant of cmpg5300.05_29 showed that expression of this gene is important for auto-aggregation, adhesion to the vaginal epithelial cells, biofilm formation and binding to mannosylated glycans. Purification of the predicted lectin domain of Cmpg5300...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27852925/anticodon-like-binding-of-the-hiv-1-trna-like-element-to-human-lysyl-trna-synthetase
#10
Sheng Liu, Roopa Comandur, Christopher P Jones, Pearl Tsang, Karin Musier-Forsyth
A critical step in the HIV-1 lifecycle involves reverse transcription of the viral genomic RNA (gRNA). Human tRNA(Lys3) serves as a primer for transcription initiation and is selectively enriched in virus particles. Human lysyl-tRNA synthetase (hLysRS) is also packaged into virions. Recently, a tRNA-like element (TLE) within the HIV-1 gRNA was shown to mimic the global tRNA fold and bind competitively to hLysRS, suggesting a mechanism of tRNA targeting to the primer binding site (PBS) and release from the synthetase...
December 2016: RNA
https://www.readbyqxmd.com/read/27834135/synthesis-and-biological-evaluation-of-benzophenone-derivatives-as-potential-hiv-1-inhibitors
#11
Zhendong Song, Ping Wang, Shanshan Huang, Changyuan Wang, Ruirui Wang, Liumeng Yang, Yuhong Zhen, Kexin Liu, Yongtang Zheng, Xiaodong Ma
BACKGROUND: Although a number of agents can achieve high response in acquired immunodeficiency syndrome (AIDS) patients, safer and more active HIV inhibitors are still needed for the growing number of patients infected with resistant HIV virus strains. GW678248, is one of the most potent benzophenone derivatives, exhibiting high potency against a panel of HIV-1 virus (wild-type, K103N mutant, Y181C, etc.) at 1 nM/L concentrations. However, the safety issues associated with rash and liver metabolic enzymes ultimately led to discontinue its further development...
November 11, 2016: Medicinal Chemistry
https://www.readbyqxmd.com/read/27829329/comparison-of-antibody-immune-responses-to-different-hiv-1-envelope-glycoprotein-mutants
#12
Jian-Dong Liu, Li Ren, Bin Ju, Wei Song, Xiang-Yang Ge, Kun-Xue Hong, Ying Liu, Wei Xu, Yan-Ling Hao, Yi-Ming Shao
The identification of immunogens is crucial for human immunodeficiency virus type 1 (HIV-1) vaccine development. In our previous study, we demonstrated that HIV-1 envelope glycoprotein mutants based on the equine infectious anemia virus (EIAV)attenuated vaccine enhance immunogenicity, both for DNA immunization alone and as a combined DNA prime-vaccinia boost immunization. An RV144 clinical trial has demonstrated that an envelope protein boost may provide some degree of protection against HIV-1 infection. In order to explore the antibody immune responses to two HIV-1 envelope glycoprotein mutants based on the EIAV vaccine and wild-type envelope glycoprotein, mice and guinea pigs were immunized using a DNA prime-protein boost immunization strategy...
November 8, 2016: Current HIV Research
https://www.readbyqxmd.com/read/27825908/functional-analysis-of-an-amp-forming-acetyl-coa-synthetase-from-leishmania-donovani-by-gene-overexpression-and-targeted-gene-disruption-approaches
#13
Neelagiri Soumya, Mitesh N Panara, Kishore Babu Neerupudi, Sushma Singh
Leishmaniasis, a neglected tropical disease is endemic in 98 countries and >350 million people are at risk of getting the infection. The existing chemotherapy of Leishmaniasis is limited due to adverse effects, resistance to existing drugs and increasing cases of HIV-Leishmaniasis co-infection. Hence, there is a need to identify novel metabolic pathways for design of new chemical entities. Acetyl-CoA synthetase (AceCS) is an enzyme of acetate metabolic pathway whose functions are unknown in Leishmania parasite...
November 5, 2016: Parasitology International
https://www.readbyqxmd.com/read/27821283/dynamic-conformational-changes-in-the-rhesus-trim5%C3%AE-dimer-dictate-the-potency-of-hiv-1-restriction
#14
Rajan Lamichhane, Santanu Mukherjee, Nikolai Smolin, Raymond F Pauszek, Margret Bradley, Jaya Sastri, Seth L Robia, David Millar, Edward M Campbell
The TRIM5α protein from rhesus macaques (rhTRIM5α) mediates a potent inhibition of HIV-1 infection via a mechanism that involves the abortive disassembly of the viral core. We have demonstrated that alpha-helical elements within the Linker 2 (L2) region, which lies between the SPRY domain and the Coiled-Coil domain, influence the potency of restriction. Here, we utilize single-molecule FRET analysis to reveal that the L2 region of the TRIM5α dimer undergoes dynamic conformational changes, which results in the displacement of L2 regions by 25 angstroms relative to each other...
November 4, 2016: Virology
https://www.readbyqxmd.com/read/27809253/developing-hiv-1-protease-inhibitors-through-stereospecific-reactions-in-protein-crystals
#15
Folasade M Olajuyigbe, Nicola Demitri, Rita De Zorzi, Silvano Geremia
Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal...
October 31, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27795437/a-helical-short-peptide-fusion-inhibitor-with-highly-potent-activities-against-hiv-1-hiv-2-and-simian-immunodeficiency-virus
#16
Shengwen Xiong, Pedro Borrego, Xiaohui Ding, Yuanmei Zhu, Andreia Martins, Huihui Chong, Nuno Taveira, Yuxian He
: HIV-2 has already spread to different regions worldwide and currently about 1-2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T-20 (Enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug-resistance and is not active on HIV-2. In this study, we firstly demonstrated that the M-T hook structure was also a vital strategy to enhance the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27771810/investigating-the-effects-of-point-mutations-on-the-affinity-between-the-cyanobacterial-lectin-microvirin-and-high-mannose-type-glycans-present-on-the-hiv-envelope-glycoprotein
#17
Rafael Conceição de Souza, Gabriela de Medeiros Muniz, Andrei Santos Siqueira, Adonis de Melo Lima, Alessandra Pereira da Silva, Evonnildo Costa Gonçalves, João Lídio da Silva Gonçalves Vianez Júnior
Human immunodeficiency virus (HIV) infections continue to exert an enormous impact on global human health. This led experts to emphasize the importance of new measures for preventing HIV infections, including the development of vaccines and novel drugs. In this context, a promising approach involves the use of lectins that can bind the surface envelope glycoprotein gp120 of HIV with high affinity, preventing viral entry. The cyanobacterial lectin microvirin (MVN) has been proposed as a candidate for development as a topical microbicide because of its ability to bind to high mannose-type glycans, potently inhibiting HIV-1 entry...
November 2016: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/27758855/core-binding-factor-%C3%AE-protects-hiv-type-1-accessory-protein-viral-infectivity-factor-from-mdm2-mediated-degradation
#18
Yusuke Matsui, Keisuke Shindo, Kayoko Nagata, Noriyoshi Yoshinaga, Kotaro Shirakawa, Masayuki Kobayashi, Akifumi Takaori-Kondo
HIV, type 1 overcomes host restriction factor apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins by organizing an E3 ubiquitin ligase complex together with viral infectivity factor (Vif) and a host transcription cofactor core binding factor β (CBFβ). CBFβ is essential for Vif to counteract APOBEC3 by enabling the recruitment of cullin 5 to the complex and increasing the steady-state level of Vif protein; however, the mechanisms by which CBFβ up-regulates Vif protein remains unclear...
November 25, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27754450/single-amino-acid-substitution-n659d-in-hiv-2-envelope-glycoprotein-env-impairs-viral-release-and-hampers-bst-2-antagonism
#19
François E Dufrasne, Catherine Lombard, Patrick Goubau, Jean Ruelle
BST-2 or tetherin is a host cell restriction factor that prevents the budding of enveloped viruses at the cell surface, thus impairing the viral spread. Several countermeasures to evade this antiviral factor have been positively selected in retroviruses: the human immunodeficiency virus type 2 (HIV-2) relies on the envelope glycoprotein (Env) to overcome BST-2 restriction. The Env gp36 ectodomain seems involved in this anti-tetherin activity, however residues and regions interacting with BST-2 are not clearly defined...
October 14, 2016: Viruses
https://www.readbyqxmd.com/read/27750153/discovery-of-novel-piperidine-substituted-indolylarylsulfones-as-potent-hiv-nnrtis-via-structure-guided-scaffold-morphing-and-fragment-rearrangement
#20
Xiao Li, Ping Gao, Boshi Huang, Zhongxia Zhou, Zhao Yu, Zheng Yuan, Huiqing Liu, Christophe Pannecouque, Dirk Daelemans, Erik De Clercq, Peng Zhan, Xinyong Liu
To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.62 μM to 0.006 μM 8 (EC50 = 6 nM) and 18 (EC50 = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV...
October 5, 2016: European Journal of Medicinal Chemistry
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