View source for Nangibotide

{{Short description|Chemical compound}}
{{Orphan|date=September 2020}}

{{Infobox drug
| drug_name          = Nangibotide
| image              = Nangibotide molecular structure.png
| IUPAC_name         = L-Leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methionine
| routes_of_administration = Intravenous; intraperitoneal
| metabolism         = Enzymatic in bloodstream
| elimination_half-life = 3 minutes
| CAS_number         = 2014384‐91‐7
| ChemSpiderID       = 64835227
| UNII=59HD7BLX9H
| ChEMBL = 4297793
| smiles = C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccc(cc1)O)C(=O)NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(C)C)N
| StdInChI=1S/C54H83N15O21S2/c1-25(2)19-29(55)47(83)65-32(9-13-38(56)71)50(86)66-33(10-14-39(57)72)51(87)67-34(12-16-43(77)78)52(88)69-36(21-44(79)80)53(89)61-26(3)46(82)59-22-40(73)62-31(11-15-42(75)76)49(85)68-35(20-27-5-7-28(70)8-6-27)48(84)60-23-41(74)63-37(24-91)54(90)64-30(45(58)81)17-18-92-4/h5-8,25-26,29-37,70,91H,9-24,55H2,1-4H3,(H2,56,71)(H2,57,72)(H2,58,81)(H,59,82)(H,60,84)(H,61,89)(H,62,73)(H,63,74)(H,64,90)(H,65,83)(H,66,86)(H,67,87)(H,68,85)(H,69,88)(H,75,76)(H,77,78)(H,79,80)/t26-,29-,30-,31-,32-,33-,34-,35-,36-,37-/m0/s1 
| StdInChIKey = JLOOQDWHNKOITN-DAHMAOPXSA-N
| chemical_formula   = C54H82N14O22S2
| molecular_weight   = 1343.439
| molecular_weight_unit = Da
| receptors          = TREM-1
}}

'''Nangibotide''' is an inhibitor of [[TREM-1]], a receptor found on certain [[granulocyte|white blood cell]]s. Activation of TREM-1 stimulates [[Systemic inflammatory response syndrome|inflammation]]. Nangibotide is therefore being investigated as a treatment for the overwhelming inflammation typically seen in severe [[sepsis]].

== Chemistry ==

Nangibotide is a 12-amino-acid polypeptide derived from [[TREML1|TLT-1]].<ref>{{cite journal |vauthors=Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M|title=A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition. |journal=British Journal of Clinical Pharmacology |date=2018 |volume=84 |issue=10 |pages=2270–2279 |doi=10.1111/bcp.13668 |pmid=29885068 |pmc=6138490 }}</ref>

== Mode of action ==

[[TREM-1]] is a receptor found on [[neutrophil]]s, [[macrophage]]s and [[monocyte]]s, key elements of the [[immune system]]. Activation of TREM-1 results in expression of [[NF-κB]], which promotes systemic [[inflammation]]. Nangibotide inhibits TREM-1, thereby preventing the inflammatory activation. Absence of TREM-1 results in vastly reduced inflammation without impairing the ability to fight infection.<ref>{{cite journal |vauthors=Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, Riether C, Siegrist M, Schneider C, Pawelski H, Gurzeler U, Ziltener P, Genitsch V, Tacchini-Cottier F, Ochsenbein A, Hofstetter W, Kopf M, Kaufmann T, [[Annette Oxenius|Oxenius A]], Reith W, Saurer L, Mueller C |title=TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. |journal=PLOS Pathog. |date=2014 |volume=10 |issue=1 |page=e1003900 |doi=10.1371/journal.ppat.1003900 |pmid=24453980 |pmc=3894224 |doi-access=free }}</ref>

== Animal models ==
LR17, a mouse equivalent of nangibotide, improves survival in mouse models of severe sepsis.<ref>{{cite journal |vauthors=Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, Massin F, Max JP, Ford J, Alauzet C, Levy B, McVicar DW, Gibot S |title=Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis. |journal=Journal of Immunology |date=1 June 2012 |volume=188 |issue=11 |pages=5585–5592 |doi=10.4049/jimmunol.1102674 |pmid=22551551 |pmc=6382278 |doi-access=free }}</ref> In a pig model of sepsis, LR12 - another animal equivalent of nangibotide - resulted in significantly improved [[haemodynamics]] and less [[organ failure]].<ref>{{cite journal |vauthors=Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, Lozniewski A, Leroy P, Tran N, Gibot S |title=Effects of a TREM-like transcript 1-derived peptide during hypodynamic septic shock in pigs. |journal=Shock |date=Feb 2013 |volume=39 |issue=2 |pages=176–182 |doi=10.1097/SHK.0b013e31827bcdfb |pmid=23324887 |s2cid=23583753 |url=https://pubmed.ncbi.nlm.nih.gov/23324887/|doi-access=free }}</ref> In monkeys, LR12 also reduced the inflammatory and hypotensive effects of sepsis.<ref>{{cite journal |vauthors=Derive M, Boufenzer A, Gibot S |title=Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate. |journal=Anesthesiology |date=April 2014 |volume=120 |issue=4 |pages=935–942 |doi=10.1097/ALN.0000000000000078 |pmid=24270127 |s2cid=10347527 |url=https://pubmed.ncbi.nlm.nih.gov/24270127/|doi-access=free }}</ref>

== Human studies ==
Nangibotide has demonstrated safety in Phase 1 (healthy volunteers)<ref>{{cite journal |vauthors=Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M|title=A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition. |journal=Br J Clin Pharmacol |date=2018 |volume=84 |issue=10 |pages=2270–2279 |doi=10.1111/bcp.13668 |pmid=29885068 |pmc=6138490 }}</ref> and Phase 2 (sick patients with septic shock)<ref>{{cite journal |vauthors=François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sánchez M, Salcedo-Magguilli M, Laterre PF |title=Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. |journal=Intensive Care Medicine |date=July 2020 |volume=46 |issue=7 |pages=1425–1437 |doi=10.1007/s00134-020-06109-z |pmid=32468087 |s2cid=218912723 |url=https://pubmed.ncbi.nlm.nih.gov/32468087/}}</ref> studies. The ASTONISH trial will examine clinical efficacy in 450 patients with septic shock.<ref>{{cite web |title=Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock (ASTONISH) |url=https://clinicaltrials.gov/ct2/show/NCT04055909 |website=ClinicalTrials.gov |publisher=US National Library of Medicine |access-date=13 July 2020}}</ref>

== References ==
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[[Category:Anti-inflammatory agents]]
[[Category:Peptides]]