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1.
Antimicrob Agents Chemother ; 57(8): 4035-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23689710

RESUMO

T-20EK is a novel fusion inhibitor designed to have enhanced α-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors.


Assuntos
Farmacorresistência Viral , Proteína gp41 do Envelope de HIV/farmacologia , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sequência de Aminoácidos , Substituição de Aminoácidos , Linhagem Celular Tumoral , Enfuvirtida , Ácido Glutâmico/metabolismo , HIV-1/genética , Humanos , Lisina/genética , Lisina/metabolismo , Dados de Sequência Molecular , Estrutura Secundária de Proteína , Eletricidade Estática
2.
Int J Biochem Cell Biol ; 45(4): 908-15, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23357451

RESUMO

T-20 (enfuvirtide) resistance is caused by the N43D primary resistance mutation at its presumed binding site at the N-terminal heptad repeat (N-HR) of gp41, accompanied by the S138A secondary mutation at the C-terminal HR of gp41 (C-HR). We have discovered that modifying T-20 to include S138A (T-20S138A) allows it to efficiently block wild-type and T20-resistant viruses, by a mechanism that involves improved binding of T-20S138A to the N-HR that contains the N43D primary mutation. To determine how HIV-1 in turn escapes T-20S138A we used a dose escalation method to select T-20S138A-resistant HIV-1 starting with either wild-type (HIV-1WT) or T-20-resistant (HIV-1N43D/S138A) virus. We found that when starting with WT background, I37N and L44M emerged in the N-HR of gp41, and N126K in the C-HR. However, when starting with HIV-1N43D/S138A, L33S and I69L emerged in N-HR, and E137K in C-HR. T-20S138A-resistant recombinant HIV-1 showed cross-resistance to other T-20 derivatives, but not to C34 derivatives, suggesting that T-20S138A suppressed HIV-1 replication by a similar mechanism to T-20. Furthermore, E137K enhanced viral replication kinetics and restored binding affinity with N-HR containing N43D, indicating that it acts as a secondary, compensatory mutation. We therefore introduced E137K into T-20S138A (T-20E137K/S138A) and revealed that T-20E137K/S138A moderately suppressed replication of T-20S138A-resistant HIV-1. T-20E137K/S138A retained activity to HIV-1 without L33S, which seems to be a key mutation for T-20 derivatives. Our data demonstrate that secondary mutations can be consistently used for the design of peptide inhibitors that block replication of HIV resistant to fusion inhibitors.


Assuntos
Substituição de Aminoácidos , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Farmacorresistência Viral/genética , Proteína gp41 do Envelope de HIV/farmacologia , HIV-1/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sequência de Aminoácidos , Fármacos Anti-HIV/química , Farmacorresistência Viral/efeitos dos fármacos , Enfuvirtida , Células HEK293 , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/genética , HIV-1/genética , HIV-1/fisiologia , Humanos , Cinética , Dados de Sequência Molecular , Mutação , Fragmentos de Peptídeos/química , Replicação Viral/efeitos dos fármacos
3.
Int J Biochem Cell Biol ; 42(9): 1482-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20580677

RESUMO

Rev, a viral regulatory protein of HIV-1, binds through its arginine-rich domain to the Rev-responsive element (RRE), a secondary structure in transcribed HIV-1 RNA. Binding of Rev to RRE mediates export of singly spliced or unspliced mRNAs from the nucleus to the cytoplasm. It has been previously shown that a certain arginine-rich peptide exhibits not only RRE-binding ability but also cell permeability and antagonism of CXCR4, one of the major coreceptors of HIV-1. Here we designed and synthesized arginine-rich peptides derived from the RNA-binding domain of Rev (Rev(34-50)) and evaluated their anti-HIV-1 activities. Rev(34-50)-A(4)C, comprising Rev(34-50) with AAAAC at the C-terminus to increase the alpha-helicity, inhibited HIV-1 entry by CXCR4 antagonism and virus production in persistently HIV-1-infected PM1-CCR5 cells. Interestingly, similar motif of human lymphotropic virus type I Rex (Rex(1-21)) also exerted moderate anti-HIV-1 activity. These results indicate that arginine-rich peptide, Rev(34-50)-A(4)C exerts dual antagonism against CXCR4 and Rev.


Assuntos
HIV-1/efeitos dos fármacos , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptores CXCR4/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Produtos do Gene rev do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Linhagem Celular , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , HIV-1/patogenicidade , Humanos , Peptídeos/química
4.
Bioorg Med Chem ; 17(14): 4916-20, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19541488

RESUMO

Feline immunodeficiency virus (FIV) is a pathogenic virus that causes an AIDS-like syndrome in the domestic cats. For viral entry and infection, fusion between the virus and the cell membrane is the critical process and this process is mediated by an envelope glycoprotein gp40. We have identified fusion inhibitory peptides from the heptad repeat-2 (HR2) of gp40. Remodeling of the original sequences using alpha-helix-inducible motifs revealed the interactive residues of gp40. Comparative analysis of HR2 peptides derived from four FIV strains demonstrated that the interactive surface of the Shizuoka strain-derived HR2 peptides provides the highest affinity of all the FIV strains examined.


Assuntos
Vírus da Imunodeficiência Felina/efeitos dos fármacos , Fusão de Membrana/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Proteínas do Envelope Viral/metabolismo , Sequência de Aminoácidos , Animais , Gatos , Dados de Sequência Molecular , Peptídeos/síntese química , Ligação Proteica , Estrutura Secundária de Proteína , Sequências Repetitivas de Aminoácidos , Relação Estrutura-Atividade , Proteínas do Envelope Viral/química
5.
Antiviral Res ; 82(3): 115-21, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19428602

RESUMO

Some mutations in the connection subdomain of the polymerase domain and in the RNase H domain of HIV-1 reverse transcriptase (RT) have been shown to contribute to resistance to RT inhibitors. However, the clinical relevance of such mutations is not well understood. To address this point we determined the prevalence of such mutations in a cohort of antiretroviral treatment-naïve patients (n=123) and assessed whether these substitutions are associated with drug resistance in vitro and in vivo. We report here significant differences in the prevalence of substitutions among subtype B, and non-subtype B HIV isolates. Specifically, the E312Q, G333E, G335D, V365I, A371V and A376S substitutions were present in 2-6% of subtype B, whereas the G335D and A371V substitutions were commonly observed in 69% and 75% of non-B HIV-1 isolates. We observed a significant decline in the viral loads of patients that were infected with HIV-1 carrying these substitutions and were subsequently treated with triple drug regimens, even in the case where zidovudine (AZT) was included in such regimens. We show here that, generally, such single substitutions at the connection subdomain or RNase H domain have no influence on drug susceptibility in vitro by themselves. Instead, they generally enhance AZT resistance in the presence of excision-enhancing mutations (EEMs, also known as thymidine analogue-associated mutations, TAMs). However, N348I, A376S and Q509L did confer varying amounts of nevirapine resistance by themselves, even in the absence of EEMs. Our studies indicate that several connection subdomain and RNase H domain substitutions typically act as pre-therapy polymorphisms.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Mutação de Sentido Incorreto , Inibidores da Transcriptase Reversa/farmacologia , Adulto , Substituição de Aminoácidos/genética , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Feminino , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral
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