Restorationof alpha-2-macroglobulin (a broad spectrum protease inhibitor) in blood can cure many diseases.

Mohammad M. Khan, MBBS., PhD. Biomark Bangladesh Foundation, 106, Hosna Centre, Gulshan Avenue, Gulshan, Dhaka 1212, Bangladesh. Author contact: aurnobaunton@gmail.com

Reviewed by Naseem Mahmud, MBBS, PhD, DTM, Obstetrics and Gynaecology, United Hospital, Dhaka, Bangladesh.

Recently, we had investigated plasma concentration of A2M, in different patients’ blood (n=31, randomly chosen) who were admitted in a hospital with different kind of diseases in Bangladesh. A2M concentration were 4 fold lower than controls (n=31). In contrast, protease activity level went up, almost 10 fold (1,2,3).

Figure. 1. Proteases were found in different diseases are belonged to following groups.  A2M inhibits all types of proteases.  

Protease inhibitors are used as drugs in many diseases for long time (4) (Table 1). Targeting drugs against different type of protease may be less effective and less successful. But targeting all types of proteases by using a broad spectrum protease inhibitor, A2M may be more beneficial in the treatment of many diseases (Figure 1). A2M inhibits not only protease(s), it is continuously removing redundant chemicals from our body, such as growth factors; cytokines; hormones; soluble beta-amyloid etc. which causes many diseases (1,2,5).

Table 1. Protease inhibitors are used as drugs in many diseases. 

Protease	Function	Disease	Drug/Status
Thrombin	Blood coagulation	Stroke	Argtroban, bivalirudin
		Coronary infarction	Ximelagartan, Melagatran
Factor Xa	Blood coagulation		Danaparoid (launched),
			DX-9065a, CI-1031(Phase-II trial)
			DPC-906, JTV-803(Phase-II trial)
			MLN-1021,PMD-3112(Phase-I trial)
Factor VIIa			NAPc2 (Phase-I trial)
HNE elastase	Cleaves elastin	SIRS	Sivelestat (Japan only)
		ARDS	Sivelestat (Phase-II trial, USA)
Complement	Inhibition	Inflammation	Nafamostat, FUT-175
HCV	HCV repication	Hepatitic C	BLIN-2061 (Phase-II trial)
			VX-950(Preclinical)
PAI (Urokinase)		Cancer	WX U K1 (Phase II)
			Aminocaproic Acid (Phase III)
		Ulcer, Psoriasis	PAI-2 (Phase-II trial)
Matriptase		Prostate Cancer	CVS-3983
Chymase	Restenosis		NK-3201 (preclinical)
Dipeptydil  Peptidase IV		Diabetes type II	LAF-237, P32/98 (Phase-II trial)
Aspartic protease inhibitors in clinic
Protease	Function	Disease	Drug/Status
HIV-1 protease	HIV replication	HIV/AIDS	Indinavir, Nelfinavir,
			Amprinavir, Ritonavir,
			Lopinavir, Saquinavir,
			Atazanavir, Fosamprenavir.
			Tipranavir (Phase III)
			(monotherapy unsuccessful)
Renin	forms Angiotensin 1	Hypertension	Aliskiren (Phase II)
BASE	forms Ab4	Alzheimers	Elan (Preclinical)
			Actelion (Preclinical)
			Locus (Preclinical)
			TGCN-001(Preclinical)
			Astex Technology (Preclinical)
			Sunesi s (Preclinical)
			De Novo (Preclinical)
Cysteine protease inhibitors in clinic
Protease	Function	Disease	Drug/Status
Rhinovirus	Viral replication	SARS	Ruprintrivir(preclinical)
SARS CoV M	Viral replication	SARS	AG7088(preclinical)
Cathepsin K	Bone resorption	Osteoporesis	AEE-58,SB-462795(Phase-II)
Caspase 1	Cytokinine release	Arthritis	VX-765 (Phase-1)
			Pralnacasan (phase II)
Caspase 3	Apoptosis	Cancer, Alzhemier	Locus Pharma
		Ischaemia, Sepsis	Novartis (preclinical)
Caspase 8	Apoptosis	Sepsis, Diabetes	IDN-6556 (Phase II)
Cruzain	parasitic replication	Trypanosomiasis	K-777, INPL-022-E7 (preclinical)
Cathepsin F, L, S			INPL-022-E7, D6 (preclinical)
Metallo protease inhibitors in clinic
Protease	Function	Disease	Drug/Status
ACE-1	Forms Angiotensin-II	Hypertension	Trandolapril, Enalapril, Captopril
NEP	Release of ANP	Hypertension	Candroxatril (discontinued)
TACE	Release of TNFa	Arthritis, MS	BMS-561392 (Phase-II)
MMP-1	Degrades matrix	Cancer	Marimistat(discontinued),
			Neovastat (Phase-III)
		Periodontitis	Periostat
MMP-2		Cancer	Rebimistat(Phase-1)
MMP-8		Osteoarthritis	Glocosamine sulphate
MMP-9		Inflammation	Rega-3G12, Biopharma
MMP-3,13			Pfizer, Novartis (preclinical)
Threonine protease inhibitors in clinic
Protease	Function	Disease	Drug/Status
Proteosome		Ischaemia	Bortezomib, MLN-519 (Phasel)

One day, we might be protected from many diseases by analyzing the level of A2M in the blood, and replenishing diminished levels of A2M in the blood by the method of treatment “A2M-ShopAnn Systems” whenever we fall ill (1,2,3, 6). The onset of a disease only occurs when A2M levels in the body are diminished, thus allowing proteases to harm the body (1, 2). Proteases begin by damaging the body’s defense systems, and, as a result, humans fall ill. Therefore, it can easily be said that, if after a blood test, A2M levels are suboptimal and these lost levels of A2M are replaced in the blood, it is possible to stop any disease at onset. The importance of analysis of the levels of A2M in the blood as well as protease(s) may be a new milestone for the direction of treatment of many diseases and open a new window in medical science (3).

Since A2M is a broad spectrum protease inhibitor, it can inhibit any kind of protease (Figure 1) released in the pathophysiology of diseases. 

This new innovation in the field of medicine may play a vital role in saving lives of all living creatures in the world such as human, plants, fishes as well as whole animal kingdom (6). 

REFERENCES

1. Khan MM, Muqueet MA, Hossain I, Khan ME, Shibli MH, Mustavi I Hossain M, Hossain ME 2016 Measurement of protease activity and concentration of a broad spectrum protease inhibitor; alpha 2 macroglobulin (A2M) in plasma of severely chronic ill patients in Bangladesh. J Clin & Exp Pathol. 6:4:288

2. Khan M.M., Muqueet M.A, Hossain I., Khan M.E., Mustavi I., Shibli M.H., Hossain M., Hossain M.E. A cross-sectional study to estimate the prevalence of protease activity in the plasma of chronically ill patients in Bangladesh and identify its predictive relationship with protease inhibitor, alpha 2-macroglobulin (A2M). 2016.  (Online Journal: Rarediseaseindia.org) http://www.rarediseasesindia.org/septicshock/proteaseprevalence

3. Khan M. A2M-Miracle Protein, the lifesaver. http://www.thebookpatch.com/BookStore/a2m-miracle-protein-the-lifesaver/e4b79078-1a67-4798-8c20-4b230e791398?isbn=9781946634290

4. Leung D, Abbenante G, Fairlie DP. Protease inhibitors: current status and future prospects. J Med Chem. 2000 Feb 10; 43(3): 305-341.

5. Armstrong PB. Proteases and protease inhibitors: a balance of activities in host-pathogen interaction. Immunobiology. 2006; 211(4):263-81.

6.  Khan MM. (Short Research Communication) 2016. A new concept on prevention and cure of diseases by a broad spectrum protease inhibitor (A2M). (Open Access journal) International Journal of Current Innovation Research, Vol. 2, Issue 11, pp 523-528, November 2016

 Submitted to Rare Diseases India on March 19, 2017.