Thesis(Ph.D.)--Case Western Reserve University, 2010 / Title from PDF (viewed on 2009-12-22) Department of Chemistry Includes abstract Includes bibliographical references and appendices Available online via the OhioLINK ETD Center

published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

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This thesis project was designed to investigate the phenotypic and genotypic variability of human immunodeficiency virus type 1 (HIV-1) drug-naive clade C reverse transcriptase (RT) and its potential impact in the development of resistance against inhibitors of RT. Five treatment-naive HIV-1 Ethiopian isolates were classified as subtype C on the basis of env gene heteroduplex mobility assays (HMA) profile and phylogenetic analysis of RT sequences. In subtype C RT, a specific KVEQ motif of silent mutations (amino acid 65, 106, 138, 161) at resistance sites was present. Two Ethiopian strains were naturally resistant to non-nucleoside RT inhibitors (NNRTI), as well as to zidovudine (ZDV), based on the natural polymorphisms of G190A and K70R, respectively. The final drug concentration that selected for NNRTI primary resistance mutations in tissue culture assays was significantly higher for clade B than clade C for each of nevirapine (NW) (10 muM versus 2 or 4 muM), efavirenz (EFV) (1muM versus 0.01muM) and delaviridine (DLV) (10muM versus 1 or 4muM), respectively. In the middle of the selection period with all the NNRTIs, subtype B viruses were harboring a mixture of both wild type and mutated forms, whereas in clade C viruses, primary resistance mutations were fully generated. Thus, we have found that clade C isolates developed more rapidly resistance (8 or 9 weeks with NVP or DLV and 13 weeks with EFV) as compared with clade B controls (at least 15 weeks with NW or DLV and 30 weeks with EFV). Odd mutations were detected during selection with NNRTIs, such as S98I, and two mutations (A62V and V75E), at sites associated to multi-drug resistance against nucleoside inhibitors (NRTIs). The substitution A62V was initially observed as a drug-naive silent mutation A62A. NW and DLV mutants were broadly cross-resistants. Following in vitro selection for drug-resistance with NNRTIs (NVP, DLV and EFV) and NRTIs [lamivudine (3TC) and ZDV], RT immunodominant regions of 14 HIV-1 s

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 126-148) Also available in print.

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: Kenneth A. Johnson. Vita. Includes bibliographical references.

Made available in DSpace on 2016-04-04T12:37:31Z (GMT). No. of bitstreams: 2 vanessa_silva_ioc_mest_2015.pdf: 7589740 bytes, checksum: f30786929de0ecb93ed285b9615ab299 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Síndrome da Imunodeficiência Adquirida Humana (AIDS) é causada pelo vírus da Imunodeficiência Humana (HIV). Existem dois tipos de vírus: HIV-1 e HIV-2, sendo o primeiro prevalente na maior parte do mundo. No ciclo biológico, o vírus utiliza três enzimas para a sua replicação: a Transcriptase Reversa (TR), a Integrase e a Protease. A TR é crucial no início do ciclo, dado que converte o RNA viral em DNA viral, se transformando em um alvo importante para o planejamento de novos inibidores. Os Inibidores da TR disponíveis no mercado são limitados, tóxicos e apresentam diversos efeitos colaterais indesejáveis, o que favorece a interrupção do tratamento causando resistência aos medicamentos. Este fato ressalta a urgência de novos fármacos mais eficientes e menos agressivos. O objetivo deste estudo é avaliar o modo de ligação de oito compostos derivados de dois inibidores nucleosídeos conhecidos da TR, o Abacavir (ABC) e a Lamivudina (3TC). Para atingir este objetivo, utilizamos metodologias computacionais como, Docking Molecular, ADME-Tox e Dinâmica Molecular. As técnicas computacionais propostas oferecem informação estrutural sobre o reconhecimento molecular de complexos receptor-ligante permitindo a realização de experimentos de desenho racional de fármacos para a obtenção de novos compostos A estrutura tridimensional da TR escolhida está disponível no banco de dados PDB em complexo com o Tenofovir, inibidor nucleotídeo da transcriptase reversa. Os resultados obtidos nos ajudam a propor os compostos 2 - (5 \2013 chloro \2013 2 - acetamidophenyl) \2013 N - [6 - (cyclopropylamino) \2013 9 - [3 - (hydroxymethyl) cyclopent \2013 1 \2013 en -1 - yl] -1,6 \2013 dihydropurin \2013 2 - yl] - 2,2 - difluoroacetamide e 2 - (2 - acetamidophenyl) - 2,2 \2013 difluoro \2013 N - {1 - [2 - (hydroxymethyl) - 1,3 \2013 oxathiolan \2013 5 - yl] \2013 2 \2013 oxopyrimidin - 4yl} acetamide análogos do Abacavir e da Lamivudina respectivamente, como os mais promissores. Paralelamente, foi identificado o modo de ligação da Lamivudina na TR por meio da Dinâmica Molecular, avaliando a evolução temporal de sua estrutura. A partir disso, torna-se possível analisar o modo de ligação de compostos que apresentem esse mesmo arcabouço / The Acquired Immuno Deficiency Syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). There are two types of virus: HIV - 1, the most predominant in the world, and HIV - 2. The HIV - 1 cycle involves the use of three enzymes for its replication: reverse transcriptase, integrase and protease. The reverse transcriptase enzyme converts viral RNA into viral DNA, a crucial step in the beginning of the cycle, making it an important target for the design of new inhibitors. The reverse transcriptase inhibitors available on the market are limited, toxic and have many undesirable side effects, which favors interruption of treatment cause resistance in drugs . These facts highlight the urg ent need for new, more efficient and less harmful drug s. The aim of this study is to evaluate the binding mode of eight analogues compounds derived from two know nucleoside reverse transcriptase inhibitors, Abacavir and Lamivudin e. To achieve this, we use the computational methods of molecular docking , ADME - Tox and molecular dynamics. The proposed computational techniques provide structural information about the receptor - ligand complex mo lecular recognition, allows the achievement the rational drug design e xperiments to obtain novel compounds. The three - dimensional structur e of the TR chosen available in PDB database in complex with Tenofovir, a known n ucleotide reverse transcriptase. The results obtained help us to propose the compounds 2 - (5 – chloro – 2 - acetamidophenyl) – n - [6 - (cyclopropyl amino) – 9 - [3 - hydroxymethyl) cyclopent – 1 – en – 1 - yl] - 1,6 – dihydropurin – 2 - yl] - 2,2 - difluoroacetamide and 2 - (2 - acetamidophenyl) - 2,2 – difluoro – n - {1 - [2 - (hydroxymethyl) - 1,3 – oxathiolan – 5 - yl] – 2 - oxopyrimidin4yl} acetamide Abacavir and Lamivudine analogues, respectively, as the most pro mising. At the same time, was analyzed the binding mode of Lamivudine through molecular dynamics to assess the evolu tion of her structure. From this, it becomes possible to analyzed the binding mode of compounds that have the same scaffold

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