Peptides Derived from the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 as Novel Inhibitors of the Viral Integrase

Gleenberg, Iris Oz; Avidan, Orna; Goldgur, Yehuda; Herschhorn, Alon; Hizi, Amnon

doi:10.1074/jbc.m414679200

Cited by 53 publications

(60 citation statements)

References 64 publications

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“…LEDGF 402-411 inhibited the enzymatic activity of IN more potently than LEDGF 361-370 did, although its affinity to IN was 3-fold weaker. This observation is because binding affinity is not the only factor that is responsible for the inhibitory activity of a molecule (K D and K i are different in many cases), as was shown for the RT inhibitors (36,37). The peptides inhibit integration in cells, do not lower the amounts of reverse transcripts, but do reduce the number of proviral copies and HIV-1 Tat-mediated transcription, showing that the peptides do not affect the early, but do halt the late, events of HIV-1 replication.…”

Section: Discussionmentioning

confidence: 91%

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Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium

Hayouka

Rosenbluh²,

Levin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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172

198

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Proteins are involved in various equilibria that play a major role in their activity or regulation. The design of molecules that shift such equilibria is of great therapeutic potential. This fact was demonstrated in the cases of allosteric inhibitors, which shift the equilibrium between active and inactive (R and T) states, and chemical chaperones, which shift folding equilibrium of proteins. Here, we expand these concepts and propose the shifting of oligomerization equilibrium of proteins as a general methodology for drug design. We present a strategy for inhibiting proteins by ''shiftides'': ligands that specifically bind to an inactive oligomeric state of a disease-related protein and modulate its activity by shifting the oligomerization equilibrium of the protein toward it. We demonstrate the feasibility of our approach for the inhibition of the HIV-1 integrase (IN) protein by using peptides derived from its cellularbinding protein, LEDGF/p75, which specifically inhibit IN activity by a noncompetitive mechanism. The peptides inhibit the DNA-binding of IN by shifting the IN oligomerization equilibrium from the active dimer toward the inactive tetramer, which is unable to catalyze the first integration step of 3 end processing. The LEDGF/ p75-derived peptides inhibit the enzymatic activity of IN in vitro and consequently block HIV-1 replication in cells because of the lack of integration. These peptides are promising anti-HIV lead compounds that modulate oligomerization of IN via a previously uncharacterized mechanism, which bears advantages over the conventional interface dimerization inhibitors.allostery ͉ protein equilibrium ͉ shiftides ͉ peptides ͉ drug design

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Section: Discussionmentioning

confidence: 91%

“…The 3Ј end processing and the strandtransfer activities of IN were performed as previously described (36,37).…”

Section: Methodsmentioning

confidence: 99%

Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium

Hayouka

Rosenbluh²,

Levin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

172

198

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“…Screening a complete library of RT-derived peptides demonstrated that two domains of about 20 amino acids mediate this interaction. Peptides bearing these amino acid sequences blocked IN enzymatic activities in vitro (7).…”

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confidence: 99%

Interaction between HIV-1 Rev and Integrase Proteins

Rosenbluh

Hayouka

Loya

et al. 2007

Journal of Biological Chemistry

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Following penetration of human immunodeficiency virus 1 (HIV-1) 3 into the host cell, reverse transcription of the viral RNA produces cDNA that is then integrated into the host chromosome (1). The integration of the viral cDNA is an essential early step in the HIV-1 life cycle. This reaction is catalyzed by the viral integrase (IN), a 32-kDa protein that is an integral part of the viral pre-integration complex (PIC) (2). The IN protein is encoded by the viral pol gene and is translated as part of a large Gag-Pol polyprotein that is processed by the viral protease (3, 4).For the integration process to occur, the viral IN must recognize specific sequences in the viral cDNA, at the termini of the long terminal repeat (LTR) elements. Retroviral integration proceeds in two steps: in the first, termed 3Ј-end processing, a dinucleotide is removed from the 3Ј-end. This reaction occurs in the cytoplasm, within the PIC (5, 6). In the next step, after entering the nucleus, the processed viral double-stranded DNA is joined to the host target DNA by an IN-mediated strandtransfer reaction.Due to its central role in HIV replication, the IN protein is an attractive target for antiviral therapy (4). Identifying specific IN inhibitors may provide a novel approach for multi-therapy strategies. Moreover, probably no cellular counterpart of IN exists in human cells and therefore, IN inhibitors should not interfere with normal cellular processes. However, only a few IN inhibitors have been described to date (4). This is in contrast to the number of inhibitors obtained against reverse transcriptase (RT) and the protease, which are the other HIV-1 enzymes that are currently used as targets for the development of anti-HIV-1 drugs (4). A promising approach for the discovery of IN inhibitors is the use of peptides derived from the IN-binding sequences of IN-interacting proteins.Specific domains within viral proteins are responsible for their interaction with host-cell receptors and with other viral and cellular proteins enabling the completion of the viral propagation cycle within the host cell (1, 6). Peptides derived from these binding domains may interfere with virus-host and virusvirus protein interactions and as such are excellent candidates as therapeutic agents. Using this approach, short peptides that inhibit IN enzymatic activity were obtained following analysis of the interaction between two of the HIV-1 proteins, RT and IN. Screening a complete library of RT-derived peptides demonstrated that two domains of about 20 amino acids mediate this interaction. Peptides bearing these amino acid sequences blocked IN enzymatic activities in vitro (7).In the present work, we observed a not yet described interaction between the HIV-1 Rev and IN proteins. The HIV-1 Rev is a karyophilic protein, which is required at the late phase of the viral life cycle for promoting nuclear export of partially spliced or un-spliced viral RNA (8, 9). Based on this finding, we identi-* This work was supported in part by grants from the Israel Science Foundat...

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“…RT-integrase interaction. On the one hand, peptide inhibitors derived from HIV-1 RT (positions 166 to 185 and 519 to 532) can efficiently inhibit 3=-end processing and the strand transfer reaction of integrase (574,575). On the other hand, a peptide derived from HIV-1 integrase (positions 46 to 65) can inhibit the polymerase activity of HIV-1 RT (576) ( Table 4).…”

Section: Development Of Hiv-derived Peptide Inhibitorsmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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Peptides Derived from the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 as Novel Inhibitors of the Viral Integrase

Cited by 53 publications

References 64 publications

Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium

Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium

Interaction between HIV-1 Rev and Integrase Proteins

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

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