Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development

The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80–100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry of research and development for CNS disorders, despite increased diagnoses of neurodegenerative disorders and the continued lack of adequate treatment options for brain injuries, stroke, neurodevelopmental disorders, and neuropsychiatric illness. However, new approaches, concurrent with the development of sophisticated bioinformatic and genomic tools, are being used to explore peptide-based therapeutics to manipulate endogenous pathways and targets, including “undruggable” intracellular protein-protein interactions (PPIs). The development of peptide-based therapeutics was previously rejected due to systemic off-target effects and poor bioavailability arising from traditional oral and systemic delivery methods. However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer’s, Parkinson’s), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them

Morphological and molecular evidence supports recognition of Danaus petilia (Stoll, 1790) (Lepidoptera: Nymphalidae) as a species distinct from D. chrysippus (Linnaeus, 1758)

The danaine butterfly Danaus chrysippus (Linnaeus, 1758) occurs widely in the Afrotropical, Oriental and Australian regions and comprises a taxonomic complex, with recent authors recognizing between one and three species. Danaus petilia (Stoll, 1790) has previously been considered to be a subspecies of D. chrysippus, but we present evidence from wing colour pattern, morphological characters and molecular data that support a recent proposal to treat D. petilia as a separate, parapatric species. The subspecies D. chrysippus cratippus (C. Felder 1860) has a limited range in Indonesia, and was until recently known in Australia from only two specimens. However, on Cobourg Peninsula in the Northern Territory of Australia, D. chrysippus cratippus and D. petilia were observed flying together in Melaleuca swampland. Comparative analysis of wing colour pattern and quantitative morphological characters of material of both taxa sampled from this geographical region of sympatry indicates at least six diagnostic features that distinguish D. petilia from D. chrysippus cratippus. Moreover, a well-sampled molecular phylogeny of the D. chrysippus complex based on sequence data from mitochondrial (cytochrome oxidase subunit 1, cytochrome b) and nuclear (wingless, elongation factor 1 alpha) genes, demonstrates that D. petilia and D. chrysippus are reciprocally monophyletic, suggesting that the two species maintain their distinctiveness even when given the spatiotemporal opportunity for interbreeding. Phylogenetic reconstruction based on molecular data and extensive sampling of the D. chrysippus complex confirms that: (1) samples of D. chrysippus cratippus from Indonesia and Australia and D. chrysippus bataviana (Moore, 1883) from Indonesia are indeed D. chrysippus; (2) specimens from India (incorrect type locality of D. petilia) are D. chrysippus; and (3) the taxon D. chrysippus dorippus (Klug, 1845) (type locality Dongala, Sudan) is not a distinct species as has recently been proposed, and is best treated either as a subspecies of D. chrysippus restricted to Africa or a genetic colour morph of D. chrysippus that extends more widely into Asia. A lectotype designation is made for Danais cratippus C. Felder, 1860, and the status of the type material and application of the name Papilio petilia is discussed. Attention is drawn to the likely clinal variation (an east west morphocline) of the D. chrysippus complex in Southeast Asia and Australia, and the dubious utility of attempting to discriminate subspecies within D. chrysippus.Funding to DJL was provided by grants NSF DEB-110380, PSCCUNY 60051-40 41, National Geographic CRE 9285-13, and a start-up grant from The City College of New York

Morphological and molecular evidence supports recognition of <i>Danaus petilia</i> (Stoll, 1790) (Lepidoptera: Nymphalidae) as a species distinct from <i>D. chrysippus</i> (Linnaeus, 1758)

<div><p>The danaine butterfly <i>Danaus chrysippus</i> (Linnaeus, 1758) occurs widely in the Afrotropical, Oriental and Australian regions and comprises a taxonomic complex, with recent authors recognizing between one and three species. <i>Danaus petilia</i> (Stoll, 1790) has previously been considered to be a subspecies of <i>D. chrysippus</i>, but we present evidence from wing colour pattern, morphological characters and molecular data that support a recent proposal to treat <i>D. petilia</i> as a separate, parapatric species. The subspecies <i>D. chrysippus cratippus</i> (C. Felder 1860) has a limited range in Indonesia, and was until recently known in Australia from only two specimens. However, on Cobourg Peninsula in the Northern Territory of Australia, <i>D. chrysippus cratippus</i> and <i>D. petilia</i> were observed flying together in <i>Melaleuca</i> swampland. Comparative analysis of wing colour pattern and quantitative morphological characters of material of both taxa sampled from this geographical region of sympatry indicates at least six diagnostic features that distinguish <i>D. petilia</i> from <i>D. chrysippus cratippus</i>. Moreover, a well-sampled molecular phylogeny of the <i>D. chrysippus</i> complex based on sequence data from mitochondrial (<i>cytochrome oxidase subunit 1</i>, <i>cytochrome b</i>) and nuclear (<i>wingless</i>, <i>elongation factor 1 alpha</i>) genes, demonstrates that <i>D. petilia</i> and <i>D. chrysippus</i> are reciprocally monophyletic, suggesting that the two species maintain their distinctiveness even when given the spatiotemporal opportunity for interbreeding. Phylogenetic reconstruction based on molecular data and extensive sampling of the <i>D. chrysippus</i> complex confirms that: (1) samples of <i>D. chrysippus cratippus</i> from Indonesia and Australia and <i>D. chrysippus bataviana</i> (Moore, 1883) from Indonesia are indeed <i>D. chrysippus</i>; (2) specimens from India (incorrect type locality of <i>D. petilia</i>) are <i>D. chrysippus</i>; and (3) the taxon <i>D. chrysippus dorippus</i> (Klug, 1845) (type locality Dongala, Sudan) is not a distinct species as has recently been proposed, and is best treated either as a subspecies of <i>D. chrysippus</i> restricted to Africa or a genetic colour morph of <i>D. chrysippus</i> that extends more widely into Asia. A lectotype designation is made for <i>Danais cratippus</i> C. Felder, 1860, and the status of the type material and application of the name <i>Papilio petilia</i> is discussed. Attention is drawn to the likely clinal variation (an east–west morphocline) of the <i>D. chrysippus</i> complex in Southeast Asia and Australia, and the dubious utility of attempting to discriminate subspecies within <i>D. chrysippus</i>.</p></div