The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors

Chong, Huihui; Xue, Yuan; Sun, Jianyuan; Qiu, Zonglin; Zhang, Meng; Waltersperger, S.; Wang, Meitian; Cui, Sheng; He, Yuxian

doi:10.1074/jbc.m112.390393

Cited by 49 publications

(95 citation statements)

References 46 publications

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“…We recently found that two residues (Met115 and Thr116) preceding the pocketbinding domain (PBD) of CHR peptides adopt a unique M-T hook structure that can greatly enhance the binding and antiviral activities (35)(36)(37)(38)(39). Our crystal structures demonstrated that the residue Thr116 can redirect the peptide chain to position Met115 above the left side of the deep pocket on the trimeric coiled coil of N-terminal helices (NHR) so that its side chain caps the pocket to stabilize the inhibitor binding (37)(38)(39).…”

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confidence: 99%

“…Our crystal structures demonstrated that the residue Thr116 can redirect the peptide chain to position Met115 above the left side of the deep pocket on the trimeric coiled coil of N-terminal helices (NHR) so that its side chain caps the pocket to stabilize the inhibitor binding (37)(38)(39). On the basis of the M-T hook structure, we generated short-peptide fusion inhibitors that mainly targeted the conserved pocket site of gp41 (37,40,41).…”

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confidence: 99%

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A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Xiong

Borrego

Ding

et al. 2017

J Virol

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Human immunodeficiency virus type 2 (HIV-2) has already spread to different regions worldwide, and currently about 1 to 2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T20 (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 first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1/2- and SIV-mediated membrane fusion. IMPORTANCE The peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors, including its potent and broad activity on HIV-1, HIV-2, and even SIV isolates, its stability as a helical, oligomeric peptide, and its high binding to diverse targets. The small size of 2P23 would benefit its synthesis and significantly reduce production cost. Therefore, 2P23 is an ideal candidate for further development, and it also provides a novel tool for studying HIV-1/2- and SIV-mediated cell fusion.

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confidence: 99%

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confidence: 99%

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Xiong

Borrego

Ding

et al. 2017

J Virol

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“…N peptides, including N36, N36 E49K , N36 L57R , and N36 E49K/L57R , and C peptides, including SC22EK, MTSC22, HP23, C34, C34 N126K , C34 E136G , C34 N126K/E136G , T20, and SFT ( Fig. 1), were synthesized using a standard solid-phase 9-fluorenylmethoxy carbonyl (FMOC) method as described previously (32). All peptides were protected by Nterminal acetylation and C-terminal amidation.…”

Section: Methodsmentioning

confidence: 99%

“…Since its discovery, the deep pocket has been considered an ideal drug target because of its high degree of conservation and essential role in viral entry (23,24); however, inhibitors that specifically target the pocket site often lack a high antiviral activity, most likely due to their weak binding affinity (25)(26)(27)(28)(29)(30). We recently found that two N-terminal residues (Met115 and Thr116) of a C peptide adopt a unique M-T hook structure, in which Thr116 redirects the peptide chain to position Met115 above the left side of the pocket so that its side chain caps the pocket to stabilize the inhibitor binding (31,32). Indeed, the M-T hook structure-modified inhibitors exhibit greatly enhanced binding and inhibitory activities (31)(32)(33)(34)(35)(36)(37).…”

mentioning

confidence: 99%

“…We recently found that two N-terminal residues (Met115 and Thr116) of a C peptide adopt a unique M-T hook structure, in which Thr116 redirects the peptide chain to position Met115 above the left side of the pocket so that its side chain caps the pocket to stabilize the inhibitor binding (31,32). Indeed, the M-T hook structure-modified inhibitors exhibit greatly enhanced binding and inhibitory activities (31)(32)(33)(34)(35)(36)(37). On the basis of the M-T hook structure, we have developed two highly potent short-peptide-based inhibitors, MTSC22 and HP23, which mainly target the deep pocket rather than the T20-or SFT-resistant sites (34,37).…”

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Genetic Pathway of HIV-1 Resistance to Novel Fusion Inhibitors Targeting the Gp41 Pocket

Sai

Chong

Xiong

et al. 2015

J Virol

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The peptide drug enfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but it easily induces drug resistance, calling for new strategies for developing effective drugs. On the basis of the M-T hook structure, we recently developed highly potent short-peptide HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the conserved gp41 pocket and possess high genetic barriers to resistance. Here, we focused on the selection and characterization of HIV-1 escape mutants of MTSC22, which revealed new resistance pathways and mechanisms. Two mutations (E49K and L57R) located at the inhibitor-binding site and two mutations (N126K and E136G) located at the C-terminal heptad repeat region of gp41 were identified as conferring high resistance either singly or in combination. While E49K reduced the C-terminal binding of inhibitors via an electrostatic repulsion, L57R dramatically disrupted the N-terminal binding of M-T hook structure and pocket-binding domain. Unlike E49K and N126K, which enhanced the stability of the endogenous viral six-helical bundle core (6-HB), L57R and E136G conversely destabilized the 6-HB structure. We also demonstrated that both primary and secondary mutations caused the structural changes in 6-HB and severely impaired the capability for HIV-1 entry. Collectively, our data provide novel insights into the mechanisms of short-peptide fusion inhibitors targeting the gp41 pocket site and help increase our understanding of the structure and function of gp41 and HIV-1 evolution. IMPORTANCEThe deep pocket on the N-trimer of HIV-1 gp41 has been considered an ideal drug target because of its high degree of conservation and essential role in viral entry. Short-peptide fusion inhibitors, which contain an M-T hook structure and mainly target the pocket site, show extremely high binding and inhibitory activities as well as high genetic barriers to resistance. In this study, the HIV-1 mutants resistant to MTSC22 were selected and characterized, which revealed that the E49K and L57R substitutions at the inhibitor-binding site and the N126K and E136G substitutions at the C-terminal heptad repeat region of gp41 critically determine the resistance phenotype. The data provide novel insights into the mechanisms of action of the M-T hook structurebased fusion inhibitors which will help further our understanding of the structure-function relationship of gp41 and molecular pathways of HIV-1 evolution and eventually facilitate the development of new anti-HIV drugs.

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Dimeric C34 Derivatives Linked through Disulfide Bridges as New HIV‐1 Fusion Inhibitors

et al. 2019

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C34, a 34‐mer fragment peptide, is contained in the HIV‐1 envelope protein gp41. A dimeric derivative of C34 linked through a disulfide bridge at its C terminus was synthesized and found to display potent anti‐HIV activity, comparable with that of a previously reported PEGylated dimer of C34REG. The reduction in the size of the linker moiety for dimerization was thus successful, and this result might shed some light on the mechanism of the suppression of six‐helix bundle formation by these C34 dimeric derivatives. Addition of a Gly‐Cys(CH2CONH2)‐Gly‐Gly motif at the N‐terminal position of a C34 monomeric derivative significantly increased the anti‐HIV‐1 activity. This moiety functions as a new pharmacophore, and this might provide a useful insight into the design of potent HIV‐1 fusion inhibitors.

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The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors

Cited by 49 publications

References 46 publications

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Genetic Pathway of HIV-1 Resistance to Novel Fusion Inhibitors Targeting the Gp41 Pocket

Dimeric C34 Derivatives Linked through Disulfide Bridges as New HIV‐1 Fusion Inhibitors

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