Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection

Bird, Gregory H.; Boyapalle, Sandhya; Wong, Terianne; Opoku-Nsiah, Kwadwo; Bedi, Raminder; Crannell, W. Christian; Perry, Alisa F.; Nguyen, Hien Thi; Sampayo, Viviana; Devareddy, Ankita; Mohapatra, Subhra; Mohapatra, Shyam S.; Walensky, Loren D.

doi:10.1172/jci71856

Cited by 64 publications

(76 citation statements)

References 46 publications

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“…A similar strategy of i.n. peptide delivery has recently been proposed for preventing the spread of respiratory syncytial virus infection to the lung (96), suggesting that this approach may be extended to other respiratory infections. The efficacy of i.n.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mathieu

Huey

Jurgens

et al. 2015

J Virol

100

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Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV H and the fusion (F) envelope glycoprotein; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad-repeat (HR) regions of F can potently inhibit MV infection at the entry stage. We show here that specific features of H's interaction with its receptors modulate the susceptibility of MV F to peptide fusion inhibitors. A higher concentration of inhibitory peptides is required to inhibit F-mediated fusion when H is engaged to its nectin-4 receptor than when H is engaged to its CD150 receptor. Peptide inhibition of F may be subverted by continued engagement of receptor by H, a finding that highlights the ongoing role of H-receptor interaction after F has been activated and that helps guide the design of more potent inhibitory peptides. Intranasal administration of these peptides results in peptide accumulation in the airway epithelium with minimal systemic levels of peptide and efficiently prevents MV infection in vivo in animal models. The results suggest an antiviral strategy for prophylaxis in vulnerable and/or immunocompromised hosts. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS)and severe neurological disease. No specific treatment is available. We have shown that parenterally delivered fusion-inhibitory peptides protect mice from lethal CNS MV disease. Here we show, using established small-animal models of MV infection, that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. Since the fusion inhibitors are stable at room temperature, this intranasal strategy is feasible even outside health care settings, could be used to protect individuals and communities in case of MV outbreaks, and could complement global efforts to control measles.

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Section: Discussionmentioning

confidence: 99%

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mathieu

Huey

Jurgens

et al. 2015

J Virol

100

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“…Various studies have reported the therapeutic potential of hydrocarbonstapled peptides in the treatment of cancer, specifically by inhibiting the NOTCH transcription factor complex [25], reactivating the p53 tumour suppressor pathway [39][40][41][42], and promoting B cell lymphoma 2 (Bcl-2)-mediated apoptosis [43]. They have also shown potential as therapeutic agents for various other diseases, such as HIV [44,45], diabetes [46], cardiovascular disease [47], and respiratory infection [48]. Two hydrocarbon-stapled peptides developed by Aileron Therapeutics are currently undergoing clinical trials for the treatment of orphan endocrine disorders and malignant tumours [49].…”

Section: Hydrocarbon Staplesmentioning

confidence: 99%

“…These doubly stapled peptides demonstrated comparable binding affinity and enhanced proteolytic stability relative to the equivalent singly stapled peptide. A fusion peptide derived from the respiratory syncytial virus and stabilised by two i, i + 7 staples was also found to be exceptionally protease resistant and highly effective in suppressing viral infection in mouse models [48].…”

Section: Multiple Staplesmentioning

confidence: 99%

Stapled peptide design: principles and roles of computation

Tan

Lane

Verma

2016

Drug Discovery Today

102

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“…By sampling alternative staple positions, interrogating cellular uptake, and correlating biochemical function with antitumor activity and mechanism of action, we have generated lead compounds that form the basis for therapeutic development (16,17,19,20). Here, we report the application of all-hydrocarbon stapling to recapitulate the native primary sequence and secondary structure of the RAS-interacting α-helix of SOS1.…”

mentioning

confidence: 99%

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

Leshchiner

Parkhitko²,

Bird

et al. 2015

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

Self Cite

148

121

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Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence-specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequencespecific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D V12 activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.R AS signaling is a critical control point for a host of cellular functions ranging from cellular survival and proliferation to cellular endocytosis and motility (1). The on or off state of RAS is dictated by nucleotide exchange. GTP-bound RAS is the activated form that engages its downstream effectors with high avidity. The endogenous GTPase activity of RAS hydrolyzes GTP to GDP and inactivates signaling. This biochemical process is further regulated by GTPase-activating proteins (GAPs) that impair RAS signaling through increasing endogenous GTPase activity and guanine-nucleotide exchange factors (GEFs) that enhance RAS signaling by facilitating GDP release and, thus, GTP association. Given the central roles of RAS in cellular growth and metabolism, it is not surprising that cancer cells usurp its prosurvival activities to achieve immortality.Activating mutations in KRAS represent the most frequent oncogenic driving force among the RAS homologs K-, N-, and H-RAS, and are associated with poor prognosis and chemoresistance (2). KRAS mutations are present in ∼30% of human tumors and at even higher frequencies in cancers of the pancreas, lung, thyroid gland, colon, and liver. For example, in pancreatic ductal adenocarcinomas (PDAC) that carry a 5-y survival rate of less than 5%, activating KRAS mutations are present in more than 90% of tumors (3). Thus, therapeutic inhibition of RAS is among the highest priority goals of the cancer field. Because oncogenic forms of KRAS typically harbor single-point mutants that stabilize its active GTP-bound form, a host of recent small molecule and peptide development efforts have been aimed at disarming this pathologic biochemical state. The extremely high affinity of KRAS for its GTP substrate has hampered the development of competitive GTP inhibitors. However, a GDP mimetic that covalently modifies the mutant cysteine of KRAS G12C represents a promising approach to plugging the nucleotid...

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Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection

Cited by 64 publications

References 46 publications

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Stapled peptide design: principles and roles of computation

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

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