Trimeric, Coiled-coil Extension on Peptide Fusion Inhibitor of HIV-1 Influences Selection of Resistance Pathways

Zhuang, Min; Wang, Wei; Feo, Christopher J. De; Vassell, Russell; Weiss, Carol D.

doi:10.1074/jbc.m111.324483

Cited by 22 publications

(61 citation statements)

References 43 publications

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“…We estimated the relative stability of different 6HBs by determining their transition mid-point temperature (T m ) in thermal denaturation studies using mixtures of N and C peptides to model 6HB interactions. Using our previous T m values [46,48], as well as additional data obtained in the current study (Table 3), we found a strong correlation between increased resistance and increased 6HB stability (Figure 2A). For example, when the T m increased 20°C, resistance increased five-fold.…”

Section: Effect Of Different Combinations Of Resistance Mutations Onsupporting

confidence: 77%

“…Their inhibitory mechanism remains unclear, but current models suggest that N peptides can interfere with HR1 coiled-coil formation, and, especially if stabilized as a trimer, can sequester the HR2 region of the pre-hairpin intermediate [44][45][46]. In either case, as with C peptides, formation of the 6HB is interrupted.…”

Section: Introductionmentioning

confidence: 99%

“…In either case, as with C peptides, formation of the 6HB is interrupted. HIV can also develop resistance to N peptides, but unlike C peptides, the resistance mutations stabilize the 6HB [46][47][48][49]. This finding presents a conundrum because some resistance mutations that increase 6HB stability might also increase peptide inhibitor affinity for gp41 and therefore enhance peptide potency.…”

Section: Introductionmentioning

confidence: 99%

“…Among the sixteen independent resistant cultures previously selected with one of three different N-peptide inhibitors, two resistance pathways emerged that were defined by having either a glutamic acid to lysine substitution at residue 560 (E560K, HXB2 numbering) in HR1 or a glutamic acid to lysine substitution at residue 648 (E648K, HXB2 numbering) in HR2 [46,48]. Using pseudovirus infectivity and entry assays, we now report that increased 6HB stability, but not faster entry kinetics, correlates with resistance.…”

Section: Introductionmentioning

confidence: 99%

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Resistance to N-peptide fusion inhibitors correlates with thermodynamic stability of the gp41 six-helix bundle but not HIV entry kinetics

et al. 2014

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Background: The HIV-1 envelope glycoprotein (Env) undergoes conformational changes that mediate fusion between virus and host cell membranes. These changes involve transient exposure of two heptad-repeat domains (HR1 and HR2) in the gp41 subunit and their subsequent self-assembly into a six-helix bundle (6HB) that drives fusion. Env residues and features that influence conformational changes and the rate of virus entry, however, are poorly understood. Peptides corresponding to HR1 and HR2 (N and C peptides, respectively) interrupt formation of the 6HB by binding to the heptad repeats of a fusion-intermediate conformation of Env, making the peptides valuable probes for studying Env conformational changes.

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Section: Effect Of Different Combinations Of Resistance Mutations Onsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Resistance to N-peptide fusion inhibitors correlates with thermodynamic stability of the gp41 six-helix bundle but not HIV entry kinetics

et al. 2014

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“…Although the effect of a single substitution was not evaluated, the authors showed that HIV-1 HXB2 pseudovirions carrying E49K/V59I double substitutions conferred ϳ400-fold resistance to PIE7-dimer. Interestingly, the E49K substitution was also selected by NHR-derived peptides (N44, N36, and IZN36) that might target both NHR and CHR sites (48,49), but the studies showed that the single E49K substitution mediated only mild resistance. In our case, this substitution repeatedly resulted in an ϳ1.5-fold change in resistance to peptide N36 (data not shown).…”

Section: Figmentioning

confidence: 99%

Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket

Sai

Chong

Qiu

et al. 2015

J Virol

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The deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N-and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors. IMPORTANCEEnfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41-dependent fusion.

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Computational prediction of anti HIV-1 peptides andin vitroevaluation of anti HIV-1 activity of HIV-1 P24-derived peptides

et al. 2014

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The world is entering the third decade of the acquired immunodeficiency syndrome (AIDS) pandemic. The primary cause of the disease has known to be human immunodeficiency virus type I (HIV-1). Recently, peptides are shown to have high potency as drugs in the treatment of AIDS. Therefore, in the present study, we have developed a method to predict anti-HIV-1 peptides using support vector machine (SVM) as a powerful machine learning algorithm. Peptide descriptors were represented based on the concept of Chou's pseudo-amino acid composition (PseAAC). HIV-1 P24-derived peptides were examined to predict anti-HIV-1 activity among them. The efficacy of the prediction was then validated in vitro. The mutagenic effect of validated anti-HIV-1 peptides was further investigated by the Ames test. Computational classification using SVM showed the accuracy and sensitivity of 96.76% and 98.1%, respectively. Based on SVM classification algorithm, 3 out of 22 P24-derived peptides were predicted to be anti-HIV-1, while the rest were estimated to be inactive. HIV-1 replication was inhibited by the three predicted anti-HIV-1 peptides as revealed in vitro, while the results of the same test on two of non-anti-HIV-1 peptides showed complete inactivity. The three anti-HIV-1 peptides were shown to be not mutagenic because of the Ames test results. These data suggest that the proposed computational method is highly efficient for predicting the anti-HIV-1 activity of any unknown peptide having only its amino acid sequence. Moreover, further experimental studies can be performed on the mentioned peptides, which may lead to new anti-HIV-1 peptide therapeutics candidates.

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Trimeric, Coiled-coil Extension on Peptide Fusion Inhibitor of HIV-1 Influences Selection of Resistance Pathways

Cited by 22 publications

References 43 publications

Resistance to N-peptide fusion inhibitors correlates with thermodynamic stability of the gp41 six-helix bundle but not HIV entry kinetics

Resistance to N-peptide fusion inhibitors correlates with thermodynamic stability of the gp41 six-helix bundle but not HIV entry kinetics

Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket

Computational prediction of anti HIV-1 peptides andin vitroevaluation of anti HIV-1 activity of HIV-1 P24-derived peptides

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