ABSTRACT
This paper investigates the contribution of Molecular Modeling to (i) predict and (ii) understand more fundamentally HIV drug resistance. Based on a new automated GenMol module, these goals are approached by Molecular Modeling Protocols (MMPs), respectively, (i) the Molecular Modeling Phenotype Protocol (MMPP) and (ii) the Molecular Modeling Phenotype-Genotype Protocol (MMGPP). Section 2 recalls clinical practice with a reference case study and Section 3 presents atomistic simulation tools. Section 4 is the heart of the paper. In Section 4.1, MMPP drug resistance prediction is based on correlations between fold resistances versus binding energies on 2959 HIV-1 complexes with 6 protease inhibitors. Based on a drug sensitivity twofold criterion, modeling prediction is able to replace long and costly phenotype tests. In Section 4.2, MMGPP enlightens drug resistance by investigating steric and energetic residues/inhibitor interaction. Section 5 gives a synthesis on modeling contribution to drug resistance prediction. In conclusion, the most promising trend consists of MMP automats that are able to suggest a real time diagnosis taking into account the history of each patient, to enrich databases and to develop therapy strategy and new drugs.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , Models, Molecular , Software , Drug Resistance, Viral/drug effects , Genotype , HIV/drug effects , HIV/enzymology , HIV/genetics , HIV Protease/chemistry , HIV Protease/metabolism , HIV Protease Inhibitors/chemistry , Molecular Structure , PhenotypeABSTRACT
The reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) is an RNA- and DNA-dependent DNA polymerase capable of copying the viral genome before it gets integrated into the human host DNA. Hence, HIV-1 RT plays a major role in viral replication and represents a key target for anti-AIDS treatments. Amongst the eleven licensed drugs that inhibit RT, eight are chain-terminating nucleoside analogues (NRTIs) that compete with their natural counterparts during the DNA polymerization process. Unfortunately, under therapeutic pressure, the HIV-1 inevitably develops resistance to these inhibitors by accumulating mutations in the viral pol gene encoding RT. Mechanisms for this resistance can be sorted in two categories, depending on the nature of the drug and the selected mutations. The first category includes mutations involving a specific alteration of the discrimination between natural nucleotides and NRTIs. The second category includes mutations able to promote the removal of the incorporated NRTI and thus repair the nascent DNA chain. This review summarizes the modes of inhibition of HIV-1 RT with NRTIs, and describes the mechanisms of resistance to these drugs, based on enzymatic data correlated to crystal structures and molecular models involving HIV-1 RT. We also give insights into different aspects of resistance such as antagonistic mutations, replication capacity, and the implications for a rational, structure-based drug design.
Subject(s)
Drug Resistance, Viral/physiology , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Pyrimidine Nucleosides/chemistry , Reverse Transcriptase Inhibitors/metabolism , Animals , Binding Sites/physiology , Drug Resistance, Viral/drug effects , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/chemistry , HIV-1/enzymology , Humans , Pyrimidine Nucleosides/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/therapeutic use , Structure-Activity RelationshipABSTRACT
SUBJECT: Chronic hepatitis B virus (HBV) infection is usually treated by interferon alpha. However, a sustained response after stopping treatment is only obtained in 30% of patients. ACTUALITY: New therapeutic nucleoside analogs have been developed, i.e. lamivudine, famciclovir, adefovir, entecavir, clevudine. However, as in HIV infection, clearance of the original hepatitis B virus with emergence of distinct resistant mutants have been observed during or after treatment with most nucleoside analogs. In this review, the underlying mechanisms of resistance and the characterisation of HBV mutants are described to optimize the best therapeutic regimen. PERSPECTIVES: Treatment of chronic HBV infection, as most of other chronic viral infection, should be based on combination therapy with a special search for the appearance of HBV mutant resistant.
Subject(s)
Hepatitis B, Chronic/drug therapy , Reverse Transcriptase Inhibitors/pharmacology , Drug Resistance , HIV Infections/complications , Hepatitis B, Chronic/pathology , HumansABSTRACT
The synthesis of new phenylalanine-2-thiophenoxy-3-pyrrolidinones is described. Anti-HIV recombinant protease assays and HIV infected cell culture assays (observation of syncytia) demonstrated the potent anti-HIV activity of this new class of pseudopeptides.
