#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Inhibition of complement activation, myeloperoxidase, NET formation and oxidant activity by PIC1 peptide variants


Autoři: Pamela S. Hair aff001;  Adrianne I. Enos aff001;  Neel K. Krishna aff001;  Kenji M. Cunnion aff001
Působiště autorů: Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States of America aff001;  Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States of America aff002;  Children's Specialty Group, Norfolk, VA, United States of America aff003;  Children’s Hospital of The King’s Daughters, Norfolk, VA, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226875

Souhrn

Background

A product of rational molecular design, PA-dPEG24 is the lead derivative of the PIC1 family of peptides with multiple functional abilities including classical complement pathway inhibition, myeloperoxidase inhibition, NET inhibition and antioxidant activity. PA-dPEG24 is composed of a sequence of 15 amino acid, IALILEPICCQERAA, and contains a monodisperse 24-mer PEGylated moiety at its C terminus to increase aqueous solubility. Here we explore a sarcosine substitution scan of the PA peptide to evaluate impacts on solubility in the absence of PEGylation and functional characteristics.

Methods

Sixteen sarcosine substitution variants were synthesized and evaluated for solubility in water. Aqueous soluble variants were then tested in standard complement, myeloperoxidase, NET formation and antioxidant capacity assays.

Results

Six sarcosine substitution variants were aqueous soluble without requiring PEGylation. Substitution with sarcosine of the isoleucine at position eight yielded a soluble peptide that surpassed the parent molecule for complement inhibition and myeloperoxidase inhibition. Substitution with sarcosine of the cysteine at position nine improved solubility, but did not otherwise change the functional characteristics compared with the parent compound. However, replacement of both vicinal cysteine residues at positions 9 and 10 with a single sarcosine residue reduced functional activity in most of the assays tested.

Conclusions

Several of the sarcosine PIC1 variant substitutions synthesized yielded improved solubility as well as a number of unanticipated structure-function findings that provide new insights. Several sarcosine substitution variants demonstrate increased potency over the parent peptide suggesting enhanced therapeutic potential for inflammatory disease processes involving complement, myeloperoxidase, NETs or oxidant stress.

Klíčová slova:

Antioxidants – Complement activation – Complement inhibitors – Complement system – Cysteine – Heme – Neutrophils – Solubility


Zdroje

1. Matsui SM, Kiang D, Ginzton N, Chew T, Geigenmuller-Gnirke U (2001) Molecular biology of astroviruses: selected highlights. Novartis Found Symp 238: 219–233; discussion 233–216. doi: 10.1002/0470846534.ch13 11444028

2. Sebire NJ, Malone M, Shah N, Anderson G, Gaspar HB, et al. (2004) Pathology of astrovirus associated diarrhoea in a paediatric bone marrow transplant recipient. J Clin Pathol 57: 1001–1003. doi: 10.1136/jcp.2004.017178 15333670

3. Bonaparte RS, Hair PS, Banthia D, Marshall DM, Cunnion KM, et al. (2008) Human astrovirus coat protein inhibits serum complement activation via C1, the first component of the classical pathway. J Virol 82: 817–827. doi: 10.1128/JVI.01847-07 17959658

4. Frank MM, Miletic VD, Jiang H (2000) Immunoglobulin in the control of complement action. Immunol Res 22: 137–146. doi: 10.1385/IR:22:2-3:137 11339351

5. Gronemus JQ, Hair PS, Crawford KB, Nyalwidhe JO, Cunnion KM, et al. (2010) Potent inhibition of the classical pathway of complement by a novel C1q-binding peptide derived from the human astrovirus coat protein. Mol Immunol 48: 305–313. doi: 10.1016/j.molimm.2010.07.012 20728940

6. Sharp JA, Hair PS, Pallera HK, Kumar PS, Mauriello CT, et al. (2015) Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats. PLoS One 10: e0132446. doi: 10.1371/journal.pone.0132446 26196285

7. Hair PS, Sass LA, Krishna NK, Cunnion KM (2017) Inhibition of Myeloperoxidase Activity in Cystic Fibrosis Sputum by Peptide Inhibitor of Complement C1 (PIC1). PLoS One 12: e0170203. doi: 10.1371/journal.pone.0170203 28135312

8. Hair PS, Cunnion KM, Krishna NK (2017) Peptide Inhibitor of Complement C1 Inhibits the Peroxidase Activity of Hemoglobin and Myoglobin. Int J Pept 2017: 9454583. doi: 10.1155/2017/9454583 29081812

9. Hair PS, Enos AI, Krishna NK, Cunnion KM (2018) Inhibition of Immune Complex Complement Activation and Neutrophil Extracellular Trap Formation by Peptide Inhibitor of Complement C1. Front Immunol 9: 558. doi: 10.3389/fimmu.2018.00558 29632531

10. Gregory Rivera M, Hair PS, Cunnion KM, Krishna NK (2018) Peptide Inhibitor of Complement C1 (PIC1) demonstrates antioxidant activity via single electron transport (SET) and hydrogen atom transfer (HAT). PLoS One 13: e0193931. doi: 10.1371/journal.pone.0193931 29499069

11. Hair PS, Rivera MG, Enos AI, Pearsall SE, Sharp JA, et al. (2017) Peptide Inhibitor of Complement C1 (PIC1) Inhibits Growth of Pathogenic Bacteria. International Journal of Peptide Research and Therapeutics 101007/s10989-017-9651-z.

12. Cunnion KM, Lee JC, Frank MM (2001) Capsule production and growth phase influence binding of complement to Staphylococcus aureus. Infect Immun 69: 6796–6803. doi: 10.1128/IAI.69.11.6796-6803.2001 11598052

13. Mauriello CT, Pallera HK, Sharp JA, Woltmann JL Jr., Qian S, et al. (2013) A novel peptide inhibitor of classical and lectin complement activation including ABO incompatibility. Mol Immunol 53: 132–139. doi: 10.1016/j.molimm.2012.07.012 22906481

14. Maitra D, Shaeib F, Abdulhamid I, Abdulridha RM, Saed GM, et al. (2013) Myeloperoxidase acts as a source of free iron during steady-state catalysis by a feedback inhibitory pathway. Free Radic Biol Med 63: 90–98. doi: 10.1016/j.freeradbiomed.2013.04.009 23624305

15. Carlin JB, Doyle LW (2001) Statistics for clinicians: 4: Basic concepts of statistical reasoning: hypothesis tests and the t-test. J Paediatr Child Health 37: 72–77. doi: 10.1046/j.1440-1754.2001.00634.x 11168875

16. Moretto A, Crisma M, Kaptein B, Broxterman QB, Toniolo C (2006) N-methylation of N(alpha)-acylated, fully C(alpha)-methylated, linear, folded peptides: synthetic and conformational aspects. Biopolymers 84: 553–565. doi: 10.1002/bip.20560 16802303

17. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT (2015) Complement System Part I—Molecular Mechanisms of Activation and Regulation. Front Immunol 6: 262. doi: 10.3389/fimmu.2015.00262 26082779


Článek vyšel v časopise

PLOS One


2019 Číslo 12
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

KOST
Koncepce osteologické péče pro gynekology a praktické lékaře
nový kurz
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Svět praktické medicíny 5/2023 (znalostní test z časopisu)

Imunopatologie? … a co my s tím???
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#