Pain therapeutics from cone snail venoms: From Ziconotide to novel non-opioid pathways

Abstract

There have been numerous attempts to develop non-opioid drugs for severe pain, but the vast majority of these efforts have failed. A notable exception is Ziconotide (Prialt®), approved by the FDA in 2004. In this review, we summarize the present status of Ziconotide as a therapeutic drug and introduce a wider framework: the potential of venom peptides from cone snails as a resource providing a continuous pipeline for the discovery of non-opioid pain therapeutics. An auxiliary theme that we hope to develop is that these venoms, already a validated starting point for non-opioid drug leads, should also provide an opportunity for identifying novel molecular targets for future pain drugs. This review comprises several sections: the first focuses on Ziconotide as a therapeutic (including a historical retrospective and a clinical perspective); followed by sections on other promising Conus venom peptides that are either in clinical or pre-clinical development. We conclude with a discussion on why the outlook for discovery appears exceptionally promising. The combination of new technologies in diverse fields, including the development of novel high-content assays and revolutionary advancements in transcriptomics and proteomics, puts us at the cusp of providing a continuous pipeline of non-opioid drug innovations for pain. SIGNIFICANCE: The current opioid epidemic is the deadliest drug crisis in American history. Thus, this review on the discovery of non-opioid pain therapeutics and pathways from cone snail venoms is significant and timely.

Keywords: Cone snail venoms; Non-opioid pain pathways; Non-opioid therapeutics; Pain; Ziconotide.

Fig. 1. The Conoidean Superfamily

Left panel: Cone snails (genus Conus) belong to the family Conidae that comprises three additional minor genera (Californiconus, Conasprella and Profundiconus). Shown are representatives from each genus. From top left to bottom right: Conus marmoreus, Conus stercusmuscarum, Conus capitaneus, Californiconus californiconus, Consprella comatosa, Conasprella memiae, Conasprella pagodus, Profundiconus profundorum, Profundiconus termachii and Profundiconus lani. Right panel: The shells of two auger snails (genus: Terebra), two turrids (genus Turridae) and members of several other families within the superfamily Conoidea are shown. From top left to bottom right: Terebra subulata, Terebra triserata, Turris grandis, Turris babylonia, Fun asp, Clavus exasperates, Veprecula polycantha and Pseudodaphnella granosa.

Fig. 2

Sequences of MVIIA (Ziconotide, Prialt®) from Conus magus, GVIA from Conus geographus and CVID (Leconotide) from Conus catus. Post-translationally modified amino acids are in blue (O: hydroxyproline, *: C-terminal amidation) and the disulfide connectivity is shown. Shells are depicted next to sequences.

Fig. 3

Alignment of Contulakin-G isolated from the venom of Conus geographus with human and zebrafish neurotensin. Post-translationally modified amino acids are shown in blue. N-terminal glutamines are modified to pyroglutamic acid (Z) and the threonine in Contulakin-G carries a galactose/N-acetylgalactosamine (Gal/GalNAc) group. C-terminal amino acids critical for neurotensin receptor binding are highlighted in green. The zebrafish hormone was predicted from a precursor sequence based on similarity to human neurotensin (Uniprot accession: A0A0A7H8E2). The shell of Conus geographus is depicted.

Fig. 4

Sequences of Vc1.1 from Conus victoriae and RgIA from Conus regius. The native peptides containing post-translational modifications (Vc1a and Reg1E) are highlighted in yellow. Disulfide connectivities are provided. O: hydroxyproline, γ: γ-carboxyglutamate, *: C-terminal amidation. Shells of C. victoriae and C. regius are depicted next to sequences.

Fig. 5

Sequences of MrIA and related peptides (MrIB and CMrVI) from Conus marmoreus. The peptide analog developed as a drug lead for pain (Xen2174) carries two additional posttranslational modifications and is shown in purple. Disulfide connectivities are provided. *: C-terminal amidation, O: hydroxyproline, Z: pyroglutamic acid.