|[교육과학기술부·한국연구재단 지정 한림대학교 생명공학연구소]
◎ 제20차 생명공학연구소 정기세미나 개최 ◎
▶ 일 시 : 2013. 03. 26(화) 오후 4시
▶ 장 소 : 생명과학관 2층(8217호)
▶ 연 자 : 김진효 박사(농촌진흥청)
▶ 주 최 : 생명공학연구소, 노화-헬스케어 사업단
▶ 강의제목 : Understanding of glycoprocessing enzyme and design of sialic acid processing enzyme inhibitor
The membrane of the influenza virus contains two immunodominant glycoproteins, hemagglutinin (HA) and neuraminidase (NA), that play key roles in viral infection and spread. HA effects attachment of the virus to the host cell via its interaction with surface sialic acids, thereby initiating entry. Once the virus has replicated, the NA cleaves sialic acids from the viral and cell surfaces, allowing the virus to spread to uninfected cells. The specific antigenic properties of the different HA and NAs are used to classify influenza type A viruses into subtypes (H1-17 and N1-9). These in turn can be categorized into two groups on the basis of phylogeny: Group 1 contains N1, N4, N5 and N8, while Group 2 contains N2, N3, N6, N7 and N9. Based on the notion that potent and specific viral NA inhibitors should function to reduce viral spread, structure-based inhibitor design programs have produced two widely used anti-influenza drugs, zanamivir (Relenza) and oseltamivir (Tamiflu). Oseltamivir figured prominently in the control of the recent pandemic. Initial design of these drugs was based upon the mimicry of the flattened transition state conformation of the sugar through incorporation of an endocyclic alkene within a carbocycle (oseltamivir) or a pyranose ring (zanamivir). Specificity for the influenza enzyme, along with additional affinity, was provided by incorporation of a guanidinium or ammonium substituent at the position corresponding to C-4 of the natural substrate to interact with a highly conserved anionic pocket at that location in the active site. These broad spectrum influenza drugs are active against NAs from group 1 and 2 influenza A strains as well as influenza B. We are now seeing the emergence of drug-resistant strains, particularly against the more widely used and structurally divergent drug oseltamivir. Mutations can be both drug- and influenza subtype- specific. The most commonly seen mutation in viruses with the N1 subtype is H275Y which interferes with binding of the isopentyl side chain of oseltamivir, but still permits binding of zanamivir and the natural substrate. Mutations most commonly detected in clinical isolates with the N2 subtype include Arg292Lys and E119V. Like the H275Y, the Arg292Lys precludes full rotation of the E276 necessary to create the hydrophobic pocket for oseltamivir to bind. In contrast, E119V confers oseltamivir specific resistance due to altered interactions with the 4-amino group. E119A,D,G mutations seen in vitro affect binding of oseltamivir and/or zanamivir, demonstrating the critical nature of the interactions of C-4 amino or guanidino group for high affinity binding. Some of the recent mutations seen in pandemic H1N1 viruses, including I223R, confer reduced sensitivity to both inhibitors. The emergence of these mutant strains highlights an urgent need for new classes of NA inhibitors that differ minimally in structure from the parent sialic acid, since the development of resistance to structurally conservative, mechanism-based inhibitors should be a much less probable event.
We report here a completely new class of specific, mechanism-based anti-influenza drugs that function via the formation of a highly stabilized covalent intermediate in the neuraminidase enzyme, and confirm this mode of action via structural and mechanistic studies. These compounds function not only in cell-based assays, but also in animal models, with efficacies comparable to that of zanamivir and with broad spectrum activity against resistant strains. Their novel mode of action and their structurally conserved and mechanism-based design provide a class of drug that should be less prone to resistance development. They therefore represent possible solutions to a major public health problem.
▶ 연사 학력 및 경력
학사 :1994-1997 경상대학교 농화학과 졸업
석사 :1998-2000 경상대학교 대학원 농화학과 졸업
박사 : 2000-2005 경상대학교 대학원 응용생명화학과 졸업
현재 : 농촌진흥청 국립농업과학원
연사분을 초청하여 제 20차 정기세미나를 개최하오니 많은 참석 부탁드리겠습니다.