Tài liệu Báo cáo khoa học: Progress for dengue virus diseases Towards the NS2B–NS3pro inhibition for

REVIEW ARTICLE

Progress for dengue virus diseases

Towards the NS2B–NS3pro inhibition for a therapeutic-based

approach

Sonia Melino and Maurizio Paci

Department of Chemical Science and Technology, University of Rome ‘Tor Vergata’, Italy

One hundred million cases of dengue fever (DF) are

estimated by the World Health Organization to

occur yearly, together with between 250 000 and

500 000 cases of dengue hemorrhagic fever (DHF).

Extensive plasma leakage in various serous cavities

of the body, including the pleura, the pericardium

and the peritoneal cavities, may result in profound

shock, the so-called dengue shock syndrome (DSS).

The case ⁄fatality rate of DHF in most countries is

about 5%, although appropriate symptomatic treat￾ment has been successful in reducing the mortality

of DHF to less than 1%. Most fatalities occur

among children and young adults. DF and DHF are

primarily diseases of tropical and subtropical areas,

but represent a typical example of a global disease.

The transmission of dengue virus (DENv) has

Keywords

dengue hemorrhagic fever; dengue virus;

NS3; protease inhibitors; vaccines; viral

diseases; viral serine protease

Correspondence

S. Melino, Dipartimento di Scienze e

Tecnologie Chimiche, Universita` di Roma

‘Tor Vergata’ via della Ricerca Scientifica,

00133 Rome, Italy

Fax: +39 0672594328

Tel: +39 0672594449

E-mail: [email protected]

(Received 22 January 2007, revised 16

March 2007, accepted 17 April 2007)

doi:10.1111/j.1742-4658.2007.05831.x

Transmitted by the Aedes aegypti mosquito, the dengue virus is the etiolog￾ical agent of dengue fever, dengue hemorrhagic fever and dengue shock

syndrome, and, as such, is a significant factor in the high death rate found

in most tropical and subtropical areas of the world. Dengue diseases are

not only a health burden to developing countries, but pose an emerging

problem worldwide. The immunopathological mechanisms appear to

include a complex series of immune responses. A rapid increase in the lev￾els of cytokines and chemical mediators during dengue disease plays a key

role in inducing plasma leakage, shock and hemorrhagic manifestations.

Currently, there are no vaccines available against dengue virus, although

several tetravalent live-attenuated dengue vaccines are in clinical phases I

or II, and prevention through vaccination has become a major priority on

the agendas of the World Health Organization and of national ministries

of health and military organizations. An alternative to vaccines is found in

therapeutic-based approaches. Understanding the molecular mechanisms of

viral replication has led to the development of potential drugs, and new

molecular viral targets for therapy are emerging. The NS3 protease domain

of the NS3 protein is responsible for processing the viral polyprotein and

its inhibition is one of the principal aims of pharmacological therapy. This

review is an overview of the progress made against dengue virus; in partic￾ular, it examines the unique properties – structural and functional – of the

NS3 protease for the treatment of dengue virus infections by the inhibition

of viral polyprotein processing.

Abbreviations

ADE, antibody-dependent enhancement; DENv, Dengue virus; DF, dengue fever; DHF, dengue hemorrhagic fever; DSS, dengue shock

syndrome; E protein, glycoprotein E; ER, endoplasmic reticulum; HCV, hepatitis C virus; NS, nonstructural; NS3pro, NS3 protease domain;

NTPase, nucleotide three phosphate hydrolase; protein C, nucleocapsid protein C; prM, protein M.

2986 FEBS Journal 274 (2007) 2986–3002 ª 2007 The Authors Journal compilation ª 2007 FEBS