This presentation discusses a newer approach to treating vascular dysfunction diseases using apomimetic peptides that mimic apolipoproteins. It provides background on lipoproteins, HDL, and apolipoproteins before discussing how short synthetic peptides called apomimetic peptides can mimic apolipoprotein functions. Several apomimetic peptides are presented that show promise in reducing atherosclerosis and improving cholesterol efflux in animal models. The presentation concludes that apomimetic peptides may prove useful as diagnostic and therapeutic agents for vascular diseases.

1. A NEWER APROCH TO TREAT VASCULAR
DYSFUNCTION DISEASES
Presented by:
Alok Kumar Soni
MS (Pharm.)
Dept. of Biotechnology

2. Flow of presentation
 Blood lipid profile,
 Lipoprotein
 HDL and its role
 Apolipoprotein
 apomimetic peptide
 Role of apomimetic peptides
 Current status
 Conclusion

3. Blood lipid profile
1. Lehninger Principle of Biochemistry.(2005) 633-634.

4. Lipoprotein
Lipoprotein
Lipid
(prosthetic group)
Phospholipid
Cholesterol
Protein Apolipoprotein
Triglycerides
1. Harper Illustrated Biochemistry. (2003) 26, 205-206.

5. General Structure of lipoprotein
1. Harper Illustrated Biochemistry. (2003) 26, 205-206.

6. Classification of Lipoproteins
 Chylomicrons
 VLDL
 IDL
 LDL
 HDL
1. Harper Illustrated Biochemistry.(2003) 26, 205-206.

7. HDL and its role
Smallest (5-17nm)
Dense 70 % protein
Synthesis in liver
It have Different proteins
Blood cholesterol
Good cholesterol
1. Clinical Biochemistry. (2012) 245, 243-248.

8. Role of HDL
1. N. Engl. J. Med. (2011) 364, 127–135.

9. Apolipoprotein
 The protein moiety of a lipoprotein
 apoA-I, apoA-II, apoC-I, apoC-II, apoC-III, and apoE
which associates with lipids and form protein: lipid
complexes
 Major is apoA-I (243 amino acid) and its
characteristics of class A amphipathic α-helixes.
 apoA-I Participate in RCT by activating LCAT-lecithin:
cholesterol acyltransferase.
1. J. Mol. Biol. (1986) 187, 325–340.

10. Apomimetic peptide
 Short synthetic peptides mimic the physiological
functions of apolipoproteins
 first peptide was 18-A (DWLKAFYDKVAEKLKEAF)
18-A, on folding it show class A amphipathic α-helix
 It was able to solublize dimyristoylphosphotidyl-
choline (1:1)
similar to those
formed by
apoA:DMPC18A DMPC COMPLEX
1. Current atherosclerosis reports. (2008)12, 96-104.

11. 1. J. Lipid Res. (1992)33, 141-166.

12. Various apomimetic peptide
• Anti-atherogenic RCT
• Anti-oxidant neutralize lipid peroxidation
• Preferred over apoA-I Economical ,small size
lesser time in treating atherosclerosis
apoA-I
Mimetic (4F )
• apoE Present in both blood and CSF
• Also use in neurological condition
• two domain 22-kDa N and 10-kDa C
• N- domain contain LDLR binding region
apoE
mimetic (E-2F)
• Apolipoprotein J secreted in extracellular space
and body fluid
• Action is likewise D-4F
apo J
mimetic
1. Four prospective American studies. Circulation. (2011)79, 8–15.
2. Journal of lipid research. (2001)42, 959-966.
3. Arteriosclerosis, thrombosis, and vascular biology. (2005) 25, 1932-1937.

13. Mechanism action of apomimetic
peptide
RCT
• Efflux
cholesterol
• Stimulate
LCAT
• Block the
degradation of
ABCA 1
Anti-oxidant
• Paraoxonase
(PON-1) in
HDL is
antioxidant
• Remove lipid
peroxide from
LDL surface
Anti-
inflammatory
• Sequestration
of oxidized
lipid and
inflammatory
mediators
• Capacity of
remodel HDL,
generating
pre-β HDL
1. Arteriosclerosis, thrombosis, and vascular biology. (2001)21, 12-27.
2. International Congress Series. (2007) 1303, 103-110.

14. Role of apomimetic peptides in
pathological condition
 RCT in Hyperlipidemic
1. Arteriosclerosis, thrombosis, and vascular biology. (2001) 21, 12-27.

15. Role in atherosclerosis
•Atherosclerosis - arterial
walls thickens as a result
of accumulation of fatty
material cholesterol
•Myocardial infarction,
angina, renal stenosis,
•Impaired function

16. Mice fed with atherogenic diet
• Injection of 5F inhibit the lesion formation without
altering lipoprotein profile.
• Treatment with D-4F rendered HDL anti-inflammatory
Hyperlipidemic mice
• L-4F decrease platelet hyper-reactivity
• 4F effectively inhibit the early atherogenesis
Hyperlipidemic monkey
• Oral D-4F reduced lipoprotein lipid peroxides
• Improved HDL anti-inflammatory ,
• Improved cholesterol efflux
1. J. Mol. Biol. (2009) 187, 325–340.

17. Role in diabetes
Streptozotocin
Type 1 diabetes
Vascular
dysfunctions
Restored to
normal
D-4F treatment
Increase level of
HO-1 and EC-SOD
1. J Lipid Res. (2008) 49, 1658-1669.

18. Role in asthma
 apoE mimetic peptides is able to deactivating lipid
oxidation products
 Play a crucial role in decreasing pulmonary
inflammation
 Anti-inflammatory effect of apoE are mediated via
LDLR dependent mechanism
1. frontiers in pharmacology. (2007) 3, 338-342.

19. Role in viral infection
 Viral infection increase in cellular content and release
in to the media of parent non-oxidized phospholipid
1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphoryl –
choline
 D-4F treatment (in influenza A infected mice)
prevented viral-induced cellular content and release,
also inhibit IL-6 release from pneumocytes
1. Circulation. (2009) 106(9),1127-1132.
2. Circulation. (2004) 110(20), 3252-3258.

20. Role in neurological disorders
Hyperlipidemia can
induce brain arteriole
inflammation through
microglia
Increase level of diffusible
chemokines can interact
with surrounding brain
cell
Increase level of diffusible
chemokines can interact
with surrounding brain
cell, resulting in cognitive
impairment
Significant reduction in
inflammation by D-4F,
improve cognitive
function
1. J Lipid Res. (2006) 47(10), 2148-2160.

21. Role in sickle cell disease and
scleroderma
SCD is chronic inflammation in which xanthine oxidase (XO) from
ischemic tissue increases vascular superoxide anion (O2*)
generation.
L-4F inhibit LDL-induced increases in O2* and decreased XO bound
to pulmonary endothelium
Scleroderma is an autoimmune, connective tissue disorder that is
characterized by impaired vascular function, Tsk-/+ mice treated
with D-4F show improve vascular function
1. J Lipid Res. (2006) 48(11), 1948-1965.

22. Current status of apomimetic peptides
Peptide Primary sequence Key finding Devolopmental
phase
2F (18A) Ac-
DWLKAFYDKVAEKLKE
AF-NH2
Failed to inhibit diet-
induced
atherosclerosis in
mice
Under research
4F Ac-
DWFKAFYDKVAEKF
KEAF-NH2
Orally available and
reduced
atherosclerotic
lesions in mice
Phase trial Novartis
ETC-642 PLVDLFRELLNELLE
ALKQKLK
Activates LCAT Phase trial Pfizer
ATI-5261 Ac-
EVRSKLEEWFAAFRE
FAEEFLARLKS-NH2
In mice it promoted
ABCA 1 dependent
cholesterol efflux
Preclinical Roche
1. Pharmacology and therapeutic. (2008) 63, 6.

23. Conclusion
HDL mimetics have been made from a variety of
peptides, lipids, and proteins. They have been studied
in a number of animal models and in early human
studies, and the results suggest that they may prove
useful in vascular dysfunction and others disease as
diagnostic and therapeutic agents.

24. Thank you
Presented by:
Alok kumar soni
MS (Pharm.) sem-1
Dept. of Biotechnology