Influenza A viruses cause epidemics and pandemics in human populations, inflicting enormous suffering and economical loss. Currently, two distinct strategies - vaccines and low molecular weight drugs - are utilized to control the spread of influenza. Vaccination offers limited protection and is hampered by logistic challenges: accurate prediction of future circulating strains and production of sufficient quantities of vaccine for large populations in a short time. Four antiviral drugs have been approved in the United States for the treatment and prophylaxis of influenza. Two of them, amantadine and rimantadine, inhibit the viral M2 ion channel protein, and other two, zanamivir and oseltamivir, inhibit the viral neuraminidase activity. Besides the limited therapeutic window, side effects and high costs, most circulating viruses are already resistant to the two M2 inhibitors and development of resistance to the neuraminidase inhibitors is inevitable if they are widely used. The need to develop novel influenza therapeutics that can prevent viral resistance or significantly reduce its incidence is urgent and compelling. We have developed bi-functional polymer-attached zanamivir and sialic acid (a competitive inhibitor of viral hemagglutinin) based on (i) the principle of combination therapy of simultaneously interfering with two distinct targets on the virus and (ii) the observation that polymeric forms of a competitive inhibitor are much more potent than the monomeric counterpart. In preliminary studies, we have shown that the bi-functional polymer-attached inhibitor is much more potent than monomeric inhibitors or mono-functional polymer-attached inhibitors. In this application, we propose to 1) enhance the antiviral activity of the polymer-attached inhibitors by systematically optimize the level of conjugation and the type and size of the polymer backbone and the linker, 2) systematically evaluate the potency of the polymer-attached inhibitors in appropriate human target cells and animal models to a broad range of influenza virus isolates, including the highly pathogenic avian viruses H5N1 and H7N7, 3) to quantitatively assess the ability of the polymer-attached inhibitors to reduce viral resistance, and 4) to elucidate the antiviral mechanisms of the polymer-attached inhibitors so as to further rationally improve their antiviral activities. It is anticipated that the proposed research will (i) yield one or more highly potent, optimized polymer-attached inhibitor(s) for future clinical development and (ii) provide a new paradigm of drug development for overcoming microbial drug resistance

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI074443-03
Application #
7658898
Study Section
Special Emphasis Panel (ZAI1-CCH-M (M1))
Program Officer
Krafft, Amy
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$747,992
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Weight, Alisha K; Belser, Jessica A; Tumpey, Terrence M et al. (2014) Zanamivir conjugated to poly-L-glutamine is much more active against influenza viruses in mice and ferrets than the drug itself. Pharm Res 31:466-74
Larson, Alyssa M; Chen, Jianzhu; Klibanov, Alexander M (2013) Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants. J Pharm Sci 102:2450-9
Nassar, Roger A; Browne, Edward P; Chen, Jianzhu et al. (2012) Removing human immunodeficiency virus (HIV) from human blood using immobilized heparin. Biotechnol Lett 34:853-6
Larson, Alyssa M; Wang, Hongmei; Cao, Yang et al. (2012) Conjugating drug candidates to polymeric chains does not necessarily enhance anti-influenza activity. J Pharm Sci 101:3896-905
Lee, Chia Min; Weight, Alisha K; Haldar, Jayanta et al. (2012) Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection. Proc Natl Acad Sci U S A 109:20385-90
Larson, Alyssa M; Hsu, Bryan B; Rautaray, Debabrata et al. (2011) Hydrophobic polycationic coatings disinfect poliovirus and rotavirus solutions. Biotechnol Bioeng 108:720-3
Weight, Alisha K; Haldar, Jayanta; Alvarez de Cienfuegos, Luis et al. (2011) Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus. J Pharm Sci 100:831-5
Haldar, Jayanta; Alvarez de Cienfuegos, Luis; Tumpey, Terrence M et al. (2010) Bifunctional polymeric inhibitors of human influenza A viruses. Pharm Res 27:259-63