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Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
The HIV-1 matrix protein (MA), whose function was originally identified in the assembly of the viral capsid, has been recognized as the nuclear targeting component of the HIV-1 preintegration complex (134,135). The viral preintegration complex consists of RNA, cDNA, integrase, reverse transcriptase, and MA protein. The 17-kDa MA protein contains a putative nuclear localizing sequence (NLS) conferring nuclear transport activity to the HIV-1 preintegration complex, when attached to a secondary transport receptor (136) (Fig. 7). A stretch of basic amino acids on the N-terminus of MA matches the four residue consensus sequence (K-R/K-X-R/K) identified from the SV40 class of NLS (120). Mutations in this N-terminal region prevent replication of HIV-1 in nondividing cells (120), confirming the role of the native NLS sequence in nuclear transport. Some HIV-1 strains also contain an auxiliary gene product, vpr, which is a redundant nuclear localizing protein and confers increased karyophilicity of the preintegration complex (137). Although a localization signal sequence has not been identified on vpr, an atypical one is suspected (135,136). Another protein that may serve a nuclear transport function is Tat, which has a nuclear localization signal sequence in addition to an RNAbinding domain (138). Transport of the HIV-1 pre-integration complex is ATP-dependent, inhibited by wheat germ agglutinin, and attenuated by competing with SV40 large T NLS or HIV MA (139). These results are consistent with a nuclear pore-mediated mechanism of entry.
Antisense Oligonucleotide-Based Therapy for HIV-1 Infection from Laboratory to Clinical Trials
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
The targets for GEM®91 are, in general, single-stranded RNA such as mRNA and genomic viral RNA. After HIV-1 enters the cell, its genome is reverse transcribed in the cytoplasm to a double-stranded DNA intermediate. This step is followed by the formation of a pre-integration complex, which carries the viral DNA into the nucleus.
Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
Another way to overcome problems stemming from a necessity to activate HCS for gene transfer mediated by Oncoviridae MoMuLV-derived vectors points to a principal distinction between Oncovidiae and lentiviridae. Lentiviridae are retroviral vectors based on human (HIV) as well as non-human (feline immunodefficiency virus, equine infectious anemia virus, simian immunodeficiency virus) lentiviruses. These viruses can actively transport the pre-integration complex from the cytoplasm into nucleus of target cells with minimal cell activation from GO to G1 of the cell cycle without division.79 The effective transduction of CD34+ CD38low as well as NOD-SCID repopulating cells and CD34+ cell population using the HIV-based vectors is well established by in vitro experiments.80-82
New designs for HIV-1 integrase inhibitors: a patent review (2018-present)
Published in Expert Opinion on Therapeutic Patents, 2023
Yoshiyuki Taoda, Shuichi Sugiyama, Takahiro Seki
It has also been reported that INLAIs can be used for functional cure of HIV-1 in addition to treatment. One approach to eradicating HIV-1 is known as the ‘Shock and Kill’ strategy, which reactivates latently infected cells and kills activated cells by cellular immune responses [107]. Another strategy is to enhance the latent virus state by blocking HIV-1 transcription and locking the HIV-1 promoter in a deep latent state via epigenetic modifications. This is called the ‘Block and Lock’ strategy employing a latency promoting agent (LPA) [108]. INLAIs have been reported to act as LPAs [109]. During HIV-1 infection, LEDGF/p75 not only supports integration as a molecular tether that connects the HIV-1 pre-integration complex to chromatin [110], but also has been reported to target HIV-1 integration units to active transcription sites [111]. This led to the idea of using INLAIs for a functional cure of HIV-1. Proviruses treated with INLAIs show a tendency to integrate away from the transcription unit and toward a more repressive chromatin environment and become resistant to reactivation by latency reversing agents (LRAs) [112]. Thus, INLAIs, which have the two possibilities of therapeutic agents and LPAs, should be developed further.
Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014–2017)
Published in Expert Opinion on Therapeutic Patents, 2018
Xiaofang Zuo, Zhipeng Huo, Dongwei Kang, Gaochan Wu, Zhongxia Zhou, Xinyong Liu, Peng Zhan
Recent research has focused on new HIV-1 IN inhibitors including those targeting non-catalytic sites of IN. HIV-1 IN interacts with the cellular transcriptional co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host chromatin enabling integration. Nowadays, more and more research labs have focused their efforts on the discovery of structurally diverse IN-LEDGF allosteric inhibitors (INLAIs), exemplified by 24–28 (Figure 4) [57,58]. Especially, compound 28 (BI-224436) was the first INLAI to advance into a phase Ia clinical trial. Unfortunately, the clinical development of 28 was halted without disclosing the reason, probably due to the enterohepatic recirculation-related PK issues [59,60]. What’s more, multiple resistance mutations, including the IN A128T mutation, have been observed for many of the disclosed quinoline-based INLAIs [61,62]. Therefore, a diverse structural class of INLAIs will be needed.
Dolutegravir plus rilpivirine dual therapy in treating HIV-1 infection
Published in Expert Opinion on Pharmacotherapy, 2018
Amedeo F. Capetti, Maria V. Cossu, Laura Paladini, Giuliano Rizzardini
DTG sodium is a chiral, non-racemic integrase strand transfer inhibitor (INSTI) with a molecular weight of 419.38 g/mol, which inhibits the replication of HIV-1 by binding to the two metal cations (Mg2+) within the catalytic active site of the integrase enzyme within the pre-integration complex, competing with the 3ʹ-terminal deoxyadenosine of the viral cDNA strand for binding. Thus, it inhibits the formation the pre-integration complex and the subsequent integration of HIV cDNA into the host DNA. DTG has an in vitro half-maximal inhibitory concentration (IC50) of 2.7 nM (compared with IC50 values of 3.3 and 6.0 nM for raltegravir, RAL, and elvitegravir, ELV, respectively). The protein-adjusted IC90 is 64 ng/mL compared with 45 ng/mL for RAL and 33 ng/mL for ELV. It dissociates from the integrase–DNA complex more slowly than RAL and ELV (mean dissociation rate constant 2.7 vs. 22 and 71 × 106 ls, respectively) [20–22].