ABSTRACT
Although Aspergillus infections pose a growing threat to immunocompromised individuals, the limited range of existing drugs does not allow efficient management of invasive aspergillosis. Moreover, drug resistance is becoming increasingly common. Given that drug discovery relies on high-quality animal studies, careful design of in vivo models for invasive aspergillosis could facilitate the identification of novel antifungals. In this review, we discuss key aspects of animal models for invasive aspergillosis, covering laboratory animal species, immune modulation, inoculation routes, Aspergillus strains, treatment strategies and efficacy assessment, to enable the reader to tailor specific protocols for different types of preclinical antifungal evaluation study.
Subject(s)
Antifungal Agents/pharmacology , Aspergillosis/drug therapy , Disease Models, Animal , Animals , Aspergillosis/microbiology , Aspergillus/drug effects , Aspergillus/isolation & purification , Drug Design , Drug Evaluation, Preclinical/methods , Drug Resistance, Fungal , HumansABSTRACT
On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.
