subject:( NNRTI)

University of Rochester

1. Muchiri, John Munderu. HIV-1 reverse transcriptase : dissociation during strand transfer and effects of Efavirenz on RNase H activity.

Degree: PhD, 2014, University of Rochester

URL: http://hdl.handle.net/1802/28457

► Human immunodeficiency virus type-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) remain subjects of global importance. There is currently no vaccine approved to protect against HIV-1/AIDS… (more)

▼ Human immunodeficiency virus type-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) remain subjects of global importance. There is currently no vaccine approved to protect against HIV-1/AIDS and the emergence of drug resistance mutants to existing antiretroviral therapies poses a serious challenge demanding the need for newer strategies. Like other retroviruses, HIV-1 converts its RNA genome into double-stranded DNA by reverse transcription and then integrates this DNA into the host genome. These processes are mediated by the viral enzymes reverse transcriptase (RT) and integrase (IN). Reverse transcription involves obligatory strand transfer events. Strand transfers are unique processes that allow both completion of reverse transcription and genetic recombination. Transfers are potential drug targets, and so it is absolutely vital to understand their mechanisms. To accomplish transfer, a growing DNA primer shifts from a donor to an acceptor template. We designed a unique primer-template system allowing measurements of strand transfer without ribonuclease H (RNase H) activity. Using it, we showed that RT dissociates during transfers, allowing the critical primer shift step to occur before RT re-binds to complete the process. Additional experiments defined the mechanisms by which the non-nucleoside RT inhibitor Efavirenz (EFV) stimulates RT ribonuclease H activity. EFV had been shown to stimulate growth of a number of drug resistant virus mutants in cell culture. We examined the mechanism of EFV stimulation in vitro. EFV stimulated viral RNase H activity of both wild type and EFV resistant mutants by increasing primary and secondary cuts. EFV increased RT binding to its RNA/DNA substrate and appeared to change the binding conformation of RT so it slid more efficiently to positions of secondary cuts. The coordinated stimulation of primary and secondary cuts most likely accelerates removal of genomic RNA, facilitating minus strand transfer and making way for plus strand DNA synthesis, key steps in converting the viral RNA to DNA. In drug resistant viruses, the overall effect of EFV on the RT is to increase cleavage efficiency. This should enhance viral replication and could explain why some drug resistant mutants grow better in the presence of the drug.

Subjects/Keywords: HIV-1; Reverse transcriptase; RNase H; Efavirenz; Strand transfer; NNRTI

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APA (6^th Edition):

Muchiri, J. M. (2014). HIV-1 reverse transcriptase : dissociation during strand transfer and effects of Efavirenz on RNase H activity. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/28457

Chicago Manual of Style (16^th Edition):

Muchiri, John Munderu. “HIV-1 reverse transcriptase : dissociation during strand transfer and effects of Efavirenz on RNase H activity.” 2014. Doctoral Dissertation, University of Rochester. Accessed March 07, 2021. http://hdl.handle.net/1802/28457.

MLA Handbook (7^th Edition):

Muchiri, John Munderu. “HIV-1 reverse transcriptase : dissociation during strand transfer and effects of Efavirenz on RNase H activity.” 2014. Web. 07 Mar 2021.

Vancouver:

Muchiri JM. HIV-1 reverse transcriptase : dissociation during strand transfer and effects of Efavirenz on RNase H activity. [Internet] [Doctoral dissertation]. University of Rochester; 2014. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/1802/28457.

Council of Science Editors:

Muchiri JM. HIV-1 reverse transcriptase : dissociation during strand transfer and effects of Efavirenz on RNase H activity. [Doctoral Dissertation]. University of Rochester; 2014. Available from: http://hdl.handle.net/1802/28457

Stellenbosch University

2. Brigg, Siobhan Ernan. Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor.

Degree: MSc, Chemistry and Polymer Science, 2017, Stellenbosch University

URL: http://hdl.handle.net/10019.1/102766

► ENGLISH ABSTRACT: HIV-1 remains the worst pandemic faced by mankind since its discovery as the causative agent of AIDS in the early 1980s. An enormous… (more)

▼ ENGLISH ABSTRACT: HIV-1 remains the worst pandemic faced by mankind since its discovery as the causative agent of AIDS in the early 1980s. An enormous amount of research has been done to find a cure, but to date there has been no success and resistance is widespread among the available treatment. This project focused on the development of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a rational design approach. The lead compound, ethyl 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole-2-carboxylate, was shown to have low nano-molar potency against HIV-1 (IC50 = 16 nM), however it had two main shortcomings which needed to be addressed; poor resistance profile and poor acid stability. Previous research had shown the resistance profile could be improved by introducing meta substitution on the phenyl moiety which interacts with Tyr181 of the NNRTI binding pocket (NNIBP). We were successful in synthesising several meta substituted phenyl derivatives of the lead compound and these were shown to be equally as potent as the lead compound. Their activity against resistant strains is yet to be determined as we are awaiting the results from biological testing. The presence of an acid labile methyl ether functionality on the molecule which was susceptible to an acid catalysed indole mediated SN1 substitution in aqueous acidic medium meant that the lead compound could never be considered as a candidate for an orally available drug. The methyl ether moiety was exchanged for a sulfide moiety and several of these derivatives were successfully synthesised. Acid stability tests showed that we were successful in our endeavour to improve the acid stability, offering an advantage over the lead compound despite a slight reduction in potency. However to completely eliminate the possibility of substitution, we replaced the methyl ether moiety for an ethyl group, successfully synthesising ethyl 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxylate and 5-chloro-3-(1-phenylpropyl)-1H-indole-2-carboxamide and we are currently awaiting the results from biological testing to determine whether this derivative is active against HIV-1. The functionality in the 2-position of the indole was also investigated through the synthesis of 5-chloro-3-(methoxy(phenyl)methyl)-1H-indole and 5-chloro-3-((methylthio)(phenyl)methyl)-1H-indole. These derivatives lacking a group in the 2-position of the indole showed significant reduction in potency. Replacement of the ethyl ester for an isobutyl ester to give isobutyl 5-chloro-3-((3,5-dimethylphenyl)(methylthio)methyl)-1H-indole-2-carboxylate, showed some maintenance of potency, however the larger side chain was not well accommodated in the NNIBP. The presence of a chiral centre on the lead compound, and all derivatives synthesised in the project, resulted in our final aim; we set out to develop a method for resolving these enantiomers. Unfortunately, although we employed a variety of different strategies, including the use of chiral auxiliaries and the classical resolution method of attempting to… Advisors/Committee Members: Pelly, Stephen, C., Blackie, Margeret, A. L., Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science..

Subjects/Keywords: HIV infections; NNRTI; Synthetic drugs; UCTD; Antiviral nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Brigg, S. E. (2017). Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor. (Masters Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/102766

Chicago Manual of Style (16^th Edition):

Brigg, Siobhan Ernan. “Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor.” 2017. Masters Thesis, Stellenbosch University. Accessed March 07, 2021. http://hdl.handle.net/10019.1/102766.

MLA Handbook (7^th Edition):

Brigg, Siobhan Ernan. “Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor.” 2017. Web. 07 Mar 2021.

Vancouver:

Brigg SE. Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor. [Internet] [Masters thesis]. Stellenbosch University; 2017. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10019.1/102766.

Council of Science Editors:

Brigg SE. Lead optimisation of an indole based HIV-1 non-nucleoside reverse transcriptase inhibitor. [Masters Thesis]. Stellenbosch University; 2017. Available from: http://hdl.handle.net/10019.1/102766

3. 星, 絢子. フラグメント分子軌道法に基づくHIV-1逆転写酵素阻害剤アルケニルジアリールメタン類の分子設計・合成・活性評価 : フラグメントブンシキドウホウニモトヅク HIV-1 ギャクテンシャコウソソガイザイアルケニルジアリールメタンルイノブンシセッケイゴウセイカッセイヒョウカ; Design, Synthesis, and Biological Evaluation of Anti HIV-1 Reverse Transcriptase Inhibitor Alkenyldiarylmethane based on Fragment Molecular Orbital Method.

Degree: 博士（薬学）, 2017, Josai University / 城西大学

URL: http://libir.josai.ac.jp/il/meta_pub/G0000284repository_JOS-PhDK74

学位授与機関：城西大学学位記番号：博甲第74号，学位の種別：博士（薬学），学位授与年月日：平成29年(2017年)3月17日 (110p.)　2018年3月31日まで要旨のみ公開

Subjects/Keywords: アルケニルジアリールメタン; NNRTI; HIV; 二重耐性変異; ファーマコフォア; FMO

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APA (6^th Edition):

星, �. (2017). フラグメント分子軌道法に基づくHIV-1逆転写酵素阻害剤アルケニルジアリールメタン類の分子設計・合成・活性評価 : フラグメントブンシキドウホウニモトヅク HIV-1 ギャクテンシャコウソソガイザイアルケニルジアリールメタンルイノブンシセッケイゴウセイカッセイヒョウカ; Design, Synthesis, and Biological Evaluation of Anti HIV-1 Reverse Transcriptase Inhibitor Alkenyldiarylmethane based on Fragment Molecular Orbital Method. (Thesis). Josai University / 城西大学. Retrieved from http://libir.josai.ac.jp/il/meta_pub/G0000284repository_JOS-PhDK74

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

星, 絢子. “フラグメント分子軌道法に基づくHIV-1逆転写酵素阻害剤アルケニルジアリールメタン類の分子設計・合成・活性評価 : フラグメントブンシキドウホウニモトヅク HIV-1 ギャクテンシャコウソソガイザイアルケニルジアリールメタンルイノブンシセッケイゴウセイカッセイヒョウカ; Design, Synthesis, and Biological Evaluation of Anti HIV-1 Reverse Transcriptase Inhibitor Alkenyldiarylmethane based on Fragment Molecular Orbital Method.” 2017. Thesis, Josai University / 城西大学. Accessed March 07, 2021. http://libir.josai.ac.jp/il/meta_pub/G0000284repository_JOS-PhDK74.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

星, 絢子. “フラグメント分子軌道法に基づくHIV-1逆転写酵素阻害剤アルケニルジアリールメタン類の分子設計・合成・活性評価 : フラグメントブンシキドウホウニモトヅク HIV-1 ギャクテンシャコウソソガイザイアルケニルジアリールメタンルイノブンシセッケイゴウセイカッセイヒョウカ; Design, Synthesis, and Biological Evaluation of Anti HIV-1 Reverse Transcriptase Inhibitor Alkenyldiarylmethane based on Fragment Molecular Orbital Method.” 2017. Web. 07 Mar 2021.

Vancouver:

星 �. フラグメント分子軌道法に基づくHIV-1逆転写酵素阻害剤アルケニルジアリールメタン類の分子設計・合成・活性評価 : フラグメントブンシキドウホウニモトヅク HIV-1 ギャクテンシャコウソソガイザイアルケニルジアリールメタンルイノブンシセッケイゴウセイカッセイヒョウカ; Design, Synthesis, and Biological Evaluation of Anti HIV-1 Reverse Transcriptase Inhibitor Alkenyldiarylmethane based on Fragment Molecular Orbital Method. [Internet] [Thesis]. Josai University / 城西大学; 2017. [cited 2021 Mar 07]. Available from: http://libir.josai.ac.jp/il/meta_pub/G0000284repository_JOS-PhDK74.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

星 �. フラグメント分子軌道法に基づくHIV-1逆転写酵素阻害剤アルケニルジアリールメタン類の分子設計・合成・活性評価 : フラグメントブンシキドウホウニモトヅク HIV-1 ギャクテンシャコウソソガイザイアルケニルジアリールメタンルイノブンシセッケイゴウセイカッセイヒョウカ; Design, Synthesis, and Biological Evaluation of Anti HIV-1 Reverse Transcriptase Inhibitor Alkenyldiarylmethane based on Fragment Molecular Orbital Method. [Thesis]. Josai University / 城西大学; 2017. Available from: http://libir.josai.ac.jp/il/meta_pub/G0000284repository_JOS-PhDK74

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universiteit Utrecht

4. Kappelhoff, B.S. Clinical pharmacological investigations of antiretroviral drugs.

Degree: 2005, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/29727

► The major aim of all studies described in this thesis is to contribute to the optimisation of antiretroviral drug treatment in HIV-infected patients by the… (more)

Subjects/Keywords: Farmacie; HIV; antiretroviral drugs; non-nucleoside reverse transcriptase inhibitor; NNRTI; protease inhibitor; PI; (population) pharmacokinetics; (clinical) pharmacology; NONMEM; bioanalysis; 2NN study

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kappelhoff, B. S. (2005). Clinical pharmacological investigations of antiretroviral drugs. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/29727

Chicago Manual of Style (16^th Edition):

Kappelhoff, B S. “Clinical pharmacological investigations of antiretroviral drugs.” 2005. Doctoral Dissertation, Universiteit Utrecht. Accessed March 07, 2021. http://dspace.library.uu.nl:8080/handle/1874/29727.

MLA Handbook (7^th Edition):

Kappelhoff, B S. “Clinical pharmacological investigations of antiretroviral drugs.” 2005. Web. 07 Mar 2021.

Vancouver:

Kappelhoff BS. Clinical pharmacological investigations of antiretroviral drugs. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2005. [cited 2021 Mar 07]. Available from: http://dspace.library.uu.nl:8080/handle/1874/29727.

Council of Science Editors:

Kappelhoff BS. Clinical pharmacological investigations of antiretroviral drugs. [Doctoral Dissertation]. Universiteit Utrecht; 2005. Available from: http://dspace.library.uu.nl:8080/handle/1874/29727

University of Debrecen

5. Samatar, Sharmake Husein. Pharmacological Advances in HIV-1 Therapy .

Degree: DE – Általános Orvostudományi Kar, University of Debrecen

URL: http://hdl.handle.net/2437/281042

► The thesis is about new and traditional treatments of HIV-1. Investigating the emerging antiretorviral drugs and comparing it with the traditional treatment ways. Reviewing the… (more)

Subjects/Keywords: HIV-1 therapy; new advances in HIV-1 therapy; NNRTI; NRTI; PI; HIV epidemiology; HIV transmission

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APA (6^th Edition):

Samatar, S. H. (n.d.). Pharmacological Advances in HIV-1 Therapy . (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/281042

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Samatar, Sharmake Husein. “Pharmacological Advances in HIV-1 Therapy .” Thesis, University of Debrecen. Accessed March 07, 2021. http://hdl.handle.net/2437/281042.

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Samatar, Sharmake Husein. “Pharmacological Advances in HIV-1 Therapy .” Web. 07 Mar 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Samatar SH. Pharmacological Advances in HIV-1 Therapy . [Internet] [Thesis]. University of Debrecen; [cited 2021 Mar 07]. Available from: http://hdl.handle.net/2437/281042.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

Council of Science Editors:

Samatar SH. Pharmacological Advances in HIV-1 Therapy . [Thesis]. University of Debrecen; Available from: http://hdl.handle.net/2437/281042

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

6. Kappelhoff, B.S. Clinical pharmacological investigations of antiretroviral drugs.

Degree: 2005, University Utrecht

URL: https://dspace.library.uu.nl/handle/1874/29727 ; URN:NBN:NL:UI:10-1874-29727 ; 1874/29727 ; urn:isbn:9039339317 ; URN:NBN:NL:UI:10-1874-29727 ; https://dspace.library.uu.nl/handle/1874/29727

► The major aim of all studies described in this thesis is to contribute to the optimisation of antiretroviral drug treatment in HIV-infected patients by the… (more)

Subjects/Keywords: HIV; antiretroviral drugs; non-nucleoside reverse transcriptase inhibitor; NNRTI; protease inhibitor; PI; (population) pharmacokinetics; (clinical) pharmacology; NONMEM; bioanalysis; 2NN study

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kappelhoff, B. S. (2005). Clinical pharmacological investigations of antiretroviral drugs. (Doctoral Dissertation). University Utrecht. Retrieved from https://dspace.library.uu.nl/handle/1874/29727 ; URN:NBN:NL:UI:10-1874-29727 ; 1874/29727 ; urn:isbn:9039339317 ; URN:NBN:NL:UI:10-1874-29727 ; https://dspace.library.uu.nl/handle/1874/29727

Chicago Manual of Style (16^th Edition):

Kappelhoff, B S. “Clinical pharmacological investigations of antiretroviral drugs.” 2005. Doctoral Dissertation, University Utrecht. Accessed March 07, 2021. https://dspace.library.uu.nl/handle/1874/29727 ; URN:NBN:NL:UI:10-1874-29727 ; 1874/29727 ; urn:isbn:9039339317 ; URN:NBN:NL:UI:10-1874-29727 ; https://dspace.library.uu.nl/handle/1874/29727.

MLA Handbook (7^th Edition):

Kappelhoff, B S. “Clinical pharmacological investigations of antiretroviral drugs.” 2005. Web. 07 Mar 2021.

Vancouver:

Kappelhoff BS. Clinical pharmacological investigations of antiretroviral drugs. [Internet] [Doctoral dissertation]. University Utrecht; 2005. [cited 2021 Mar 07]. Available from: https://dspace.library.uu.nl/handle/1874/29727 ; URN:NBN:NL:UI:10-1874-29727 ; 1874/29727 ; urn:isbn:9039339317 ; URN:NBN:NL:UI:10-1874-29727 ; https://dspace.library.uu.nl/handle/1874/29727.

Council of Science Editors:

Kappelhoff BS. Clinical pharmacological investigations of antiretroviral drugs. [Doctoral Dissertation]. University Utrecht; 2005. Available from: https://dspace.library.uu.nl/handle/1874/29727 ; URN:NBN:NL:UI:10-1874-29727 ; 1874/29727 ; urn:isbn:9039339317 ; URN:NBN:NL:UI:10-1874-29727 ; https://dspace.library.uu.nl/handle/1874/29727

7. 김, 시연. Characteristic and Determinants of Discordant Virological and Immunological Responses to Antiretroviral Therapy in ART naive patients in Korean HIV infected patients.

Degree: 2014, Ajou University

URL: http://repository.ajou.ac.kr/handle/201003/10935 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000017666

Master Advisors/Committee Members: 대학원 의학과, 201224099, 김, 시연.

Subjects/Keywords: viral suppression; immune restoration; discordant response; low nadir CD4 T cell count; concurrent TB co-infection; hepatitis B co-infection; Initial ART regimen cotaining NNRT1; low body mass index (BMI); 바이러스 감소; 면역학적인 회복; 부조화반응; 낮은 기저 CD4 T세포의 수; 활동성 결핵의 동시감염; B형 간염바이러스 동시 감염; NNRTI 병합요법; 체질량지수

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APA (6^th Edition):

김, �. (2014). Characteristic and Determinants of Discordant Virological and Immunological Responses to Antiretroviral Therapy in ART naive patients in Korean HIV infected patients. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/10935 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000017666

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

김, 시연. “Characteristic and Determinants of Discordant Virological and Immunological Responses to Antiretroviral Therapy in ART naive patients in Korean HIV infected patients.” 2014. Thesis, Ajou University. Accessed March 07, 2021. http://repository.ajou.ac.kr/handle/201003/10935 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000017666.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

김, 시연. “Characteristic and Determinants of Discordant Virological and Immunological Responses to Antiretroviral Therapy in ART naive patients in Korean HIV infected patients.” 2014. Web. 07 Mar 2021.

Vancouver:

김 �. Characteristic and Determinants of Discordant Virological and Immunological Responses to Antiretroviral Therapy in ART naive patients in Korean HIV infected patients. [Internet] [Thesis]. Ajou University; 2014. [cited 2021 Mar 07]. Available from: http://repository.ajou.ac.kr/handle/201003/10935 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000017666.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

김 �. Characteristic and Determinants of Discordant Virological and Immunological Responses to Antiretroviral Therapy in ART naive patients in Korean HIV infected patients. [Thesis]. Ajou University; 2014. Available from: http://repository.ajou.ac.kr/handle/201003/10935 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000017666

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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