Novel prodrugs for treatment of human CMV infection

Award Information
Agency:
Department of Health and Human Services
Branch:
N/A
Amount:
$591,457.00
Award Year:
2010
Program:
SBIR
Phase:
Phase I
Contract:
1R43AI091216-01
Agency Tracking Number:
AI091216
Solicitation Year:
2010
Solicitation Topic Code:
NIAID
Solicitation Number:
PHS2010-2
Small Business Information
TSRL, INC.
TSRL, INC., 540 AVIS DR, STE A, ANN ARBOR, MI, -
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
156551699
Principal Investigator
 JOHN HILFINGER
 (734) 663-4233
 JHILFINGER@TSRLINC.COM
Business Contact
 JOHN HILFINGER
Phone: (734) 663-4233
Email: jhilfinger@tsrlinc.com
Research Institution
N/A
Abstract
DESCRIPTION (provided by applicant): As a result of the widespread use of antiviral prophylaxis and pre-emptive therapy, the incidence and severity of human cytomegalovirus (HCMV) disease and its indirect effects have been significantly reduced. However, there is an increasing recognition of antiviral drug resistance. In particular, with the advent of oral ganciclovir (GCV) prophylaxis against HCMV, concerns about emergence of GCV resistance (GCV-R) have been raised. GCV-R can be successfully treated with nucleotide phosphonate drugs such as Cidofovir (CDV) and 9-(S)-(3- hydroxy-2-phosphonomethoxy-propyl)adenine (HPMPA). However, these drugs are significantly limited as oral therapeutics because, as a group, they are poorly absorbed when administered orally. We have developed a prodrug strategy designed to improve the oral absorption of the nucleotide phosphonate drugs, CDV and HPMPA, such that they will be effective anti-HCMV oral therapeutic agents. In the phase 1 portion of the project, we propose to synthesize a novel series of CDV and HPMPA prodrugs and evaluate their stability, metabolism and antiviral activity against sensitive and GCV-R resistant strains of CMV. Those prodrugs showing good stability and simplified metabolism will be tested for oral bioavailability. This work will lay the scientific foundation for development of an effective, oral agent against ganciclovir resistant HCMV. For this project, we have established collaborations with Prof. Charles McKenna (prodrug design and synthesis) at the University of Southern California and Prof. John Drach (virological studies) at the University of Michigan. PUBLIC HEALTH RELEVANCE: There is an increasing need for new drugs that are effective against drug-resistant strains of the human cytomegalovirus that are becoming more numerous as long term treatments against the virus are developed. A series of new drugs is available but they are not suitable for commercialization because they are not well absorbed when given orally. Thus, the goal of this work is to modify these new drugs such that they are well absorbed when taken orally and will be effective against the human cytomegalovirus.

* information listed above is at the time of submission.

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